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Recent Updates on Viral Oncogenesis: Available Preventive and Therapeutic Entities
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Recent Updates on Viral Oncogenesis: Available Preventive and Therapeutic Entities
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  • Shivam Chowdhary
    Shivam Chowdhary
    Department of Industrial Microbiology, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj 211007, Uttar Pradesh India
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  • Rahul Deka
    Rahul Deka
    Department of Bioengineering and Biotechnology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India
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  • Kingshuk Panda
    Kingshuk Panda
    Department of Applied Microbiology, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India
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  • Rohit Kumar
    Rohit Kumar
    Department of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Greater Noida 201310, Uttar Pradesh, India
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  • Abhishikt David Solomon
    Abhishikt David Solomon
    Department of Molecular & Cellular Engineering, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj 211007, Uttar Pradesh, India
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  • Jimli Das
    Jimli Das
    Centre for Biotechnology and Bioinformatics, Dibrugarh University, Assam 786004, India
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    Supriya Kanoujiya
    School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
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    Ashish Kumar Gupta
    Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110029, India
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    Somya Sinha
    Department of Biotechnology, Graphic Era Deemed to Be University, Dehradun 248002, Uttarakhand, India
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  • Janne Ruokolainen*
    Janne Ruokolainen
    Department of Applied Physics, School of Science, Aalto University, 02150 Espoo, Finland
    *Email: [email protected]
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  • Kavindra Kumar Kesari*
    Kavindra Kumar Kesari
    Department of Applied Physics, School of Science, Aalto University, 02150 Espoo, Finland
    Division of Research and Development, Lovely Professional University, Phagwara 144411, Punjab, India
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0003-3622-9555
  • Piyush Kumar Gupta*
    Piyush Kumar Gupta
    Department of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Greater Noida 201310, Uttar Pradesh, India
    Department of Biotechnology, Graphic Era Deemed to Be University, Dehradun 248002, Uttarakhand, India
    Faculty of Health and Life Sciences, INTI International University, Nilai 71800, Malaysia
    *Email: [email protected]
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Molecular Pharmaceutics

Cite this: Mol. Pharmaceutics 2023, 20, 8, 3698–3740
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https://doi.org/10.1021/acs.molpharmaceut.2c01080
Published July 24, 2023

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Abstract

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Human viral oncogenesis is a complex phenomenon and a major contributor to the global cancer burden. Several recent findings revealed cellular and molecular pathways that promote the development and initiation of malignancy when viruses cause an infection. Even, antiviral treatment has become an approach to eliminate the viral infections and prevent the activation of oncogenesis. Therefore, for a better understanding, the molecular pathogenesis of various oncogenic viruses like, hepatitis virus, human immunodeficiency viral (HIV), human papillomavirus (HPV), herpes simplex virus (HSV), and Epstein-Barr virus (EBV), could be explored, especially, to expand many potent antivirals that may escalate the apoptosis of infected malignant cells while sparing normal and healthy ones. Moreover, contemporary therapies, such as engineered antibodies antiviral agents targeting signaling pathways and cell biomarkers, could inhibit viral oncogenesis. This review elaborates the recent advancements in both natural and synthetic antivirals to control viral oncogenesis. The study also highlights the challenges and future perspectives of using antivirals in viral oncogenesis.

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1. Introduction

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The human body is phenomenal specimen with an intricate signaling pathway network. The body has its own defense mechanism to fight against viruses and/or disease-causing agents. Suppressing the body’s defense mechanisms, cells can start behaving abnormally and divide in a malignant mode. This may lead to cancer in the human body. The formation of cancer malignancy does not rely on one aspect. It involves a wide range of interconnected factors such as genetic alterations, environmental exposures, and lifestyle factors. (1) Although, a class of cancer-causing viruses may develop cancers in humans due to oncogenic virus infections. (2) Among all types of cancer, the oncogenic virus triggers the formation of 10–20% of human cancers. (3,4) Viruses are known to replicate only when they control the host mechanisms in their favor. The characteristic feature of oncogenic viruses is the induction of viral tumorigenesis that helps in the propagation of malignancy from infected cells to healthy cells. (2) Oncogenic viruses can stimulate cancer formation with the help of several cofactors, such as persistent inflammation, suppression of cancer-specific immune agents, and involvement of cancer-causing mutagens. (5) Inflammatory signals released by infected cells act as a gateway for viral tumorigenesis. White blood cells of the immune system get alerted and help to clear the infected cells. However, with persistent or chronic inflammation, clearing and repairing such cells remain unchecked, thus leading to severe DNA damage with multiple mutational events that pave the way for cancer. (6) Following inflammation, oncogenic viruses can counter the protective action of p53, retinoblastoma tumor-suppressing pathways. (7) The addition of environmental exposure to mutagens accelerates the process of viral tumorigenesis.
Viral oncogenes can be grouped into two main categories: first replicating their genetic material (oncogenic DNA viruses) and second, replicating their genetic information. (8) Oncogenic DNA viruses include Epstein–Barr virus (EPV), hepatitis B virus (HBV), human papillomavirus (HPV), Merkel cell polyomavirus (MCPyV), and human herpesvirus-8 (HHV-8). Additionally, oncogenic RNA viruses encompass diseases like hepatitis C (HCV) and human T-cell lymphotropic virus type 1 (HTLV-1) (Figure 1). The characteristic feature of oncogenic DNA viruses is to activate the DNA damage response pathway (DDR). DDR is crucial for DNA repairing of damaged cells induced by viral tumorigenesis. (8) Their inactivation delays the cell cycle and helps the virus to skip the apoptotic pathways, thus favoring the propagation of oncogenic DNA viruses. (9) The need to prevent the spread of viral tumorigenesis has become a matter of deep concern in recent years. Antiviral therapeutics and viral vaccines are able to specify the spread of malignant cells and induce localized killing of malignant cells. Along with the development of novel antiviral therapies, there is an evident change in the pathogenicity pattern of oncogenic viruses that needs to be investigated simultaneously.

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Figure 1. Various oncogenic viral strains have taken various pathways to infect the host organism, leading to cancerous proliferation (Created in Biorender).

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This review discusses the major discoveries in recent times concerning antiviral therapies along with the analysis of viral tumorigenic pathways. Developing novel antiviral therapeutics detrimental to preventing the spread of viral-induced cancers.

2. Viruses Associated with Oncogenesis

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2.1. Hepatitis B Virus (HBV)

Studies over the past few decades revealed that HBV infection has been proven to promote disease progression via various mechanisms. HBV is an epidemic viral disease prevalent in many regions across the globe, with varying infection rates of 10–40% in New Zealand and Pacific Island countries like Fiji to 0.1% in the United States. HBV infection occurs more prominently in males with age group of 25–45-year. The prevalence percentage is recorded to be more in the urban areas of the United States. A similar age band of 25–45-year-old males are reported to be infected with HBV in the European subcontinent. Males in the 15–25 age band are also reported to be infected by HBV. Reports on infection criteria have suggested that the incidence rate of HBV is lower in females, with a caseload of as much as 0.58 compared to 1.33 cases per 100,000 in the population settings. The prevalence of hepatitis B surface antigen (HBsAg) determines the endemicity of HBV globally. The high endemic locations accounting for almost 50% of HBV-related cases belong to the African subcontinent, Asian subcontinent, the Great Amazon region, and part of Middle Eastern nations wherein the HBsAg rate is recorded to be at a whopping ≥ 8%. The low endemic rate locations, accounting for 10–12% of HBV-related cases, belong to the European subcontinent, the United States, and Australia, wherein the HBsAg rate is recorded as low as < 1%. (10,11) Furthermore, this causes hepatocytes to become cancerous over time. Several variables have been implicated in the etiology of HBV-associated HCC, including integrating HBV genes into host cells, causing genomic instability due to mutation and activating signaling pathways promoting malignancy. Studies have shown that the hepatitis B virus is closely related to retroviruses and consists of a compact, partially double-stranded DNA molecule. (12) The genome size is estimated to be around 3.2 kilobase pairs. Its framework is similar to the hepatotropic lineage of DNA viruses, classified in the genus Orthohepadnavirus and the family hepadnaviridae.
Based on the sequenced analogy of HBV, it is classified into 8 genotypes, and each genotype possesses different topographic dissemination. An infected serum consists of 3 virion types that can be visualized under an electron microscope. Among them, 2 virion types have small globular arrangements with filaments of different lengths with a width of 22 nm and a diameter of 20 nm. (13) The filaments and spheres of the virions consist of the hepatitis B surface (HBsAg) as antigen and host-originated lipids. Still, they do not contain viral nucleic acid, so they are non-infectious. (14) The third virion type and Dane particles (infectious HBV virus particles) have a spherically double-layered structure with a diameter of 42 nm and comprise a lipid coating containing HBsAg, which encloses the polymerase complex encoded by the virus and the viral DNA. The viral polymerase is bonded covalently to the 5′ terminus of the strand, which is negatively charged. (15)
The ORF (open reading frame) of the regulatory protein HBx or PreS2 can be transcribed and maintained in most of the unified subviral HBV genomes. (16) The HBx gene is a tiny peptide (17 KDa) preserved in hepatitis viral strains of mammals and present at a minimum level during acute and chronic hepatitis. Recently, DHBV (duck hepatitis B virus) was recognized as a regulative protein similar to HBx (17) where HBx has been known as a crucial viral protein in the carcinogen process related to HBV, (18,19) which could significantly affect the HBx target. Knowing about the possible role of HBx in viral malignancy, the research shifted its focus to HBX’s intervention with a signal transduction cascade that impacts cell cycle regulation, proliferation, or apoptosis. However, it should be recalled that the overexpression of HBx stimulates those conditions which are different from the infected cells, reflecting the overall genetic makeup. In particular, HBx can promote cell proliferation, which has been fully confirmed. (20)
On the contrary, the transport of the entire HBV genome containing the regulatory proteins HBx and PreS2 tends to inhibit the progression of the cell cycle. (21) There are reports about the obstruction of HBx on protein kinase C signaling. The inspection of the protein kinase C (PKC)/HBx interaction is one example of evidence that targeted the interference of HBx on the signal cascade and correlated it with the putative effect of HBx on HBV-related oncogenesis. Some studies indicate that HBx does not affect PKC activity, nor that PKC is important for HBx-dependent transcriptional instigation. (22) In contrast, there is also evidence describing the dependence of HBx on PKC stimulation, which has been satisfied by an increased level of DAG in HBx-processing cells. This implies that PKC is crucial in HBx-dependent stimulation of NF-kB or AP1. (23) A persuasive aspect of HBx-dependent PKC stimulation that is decisive model of HBx and can be derived from HBV-dependent oncogenesis.
According to the two-step malignant model, (24,25) HBx-dependent PKC activation can play a role similar to that of a tumor promoter, regardless of whether it acts similarly to a tumor promoter. (24,25) Experiments in transgenic mice showed strong evidence that HBx may function like a tumor promoter. Compared with wild-type control animals, the brilliance of HBx transgenes or disclosure of these transgenes to mutagens (diethylnitrosamine) results in a significant elevation in preneoplastic contusions. (26) The tumor promoter-like role of HBx is not necessarily needed to stimulate PKC. Pathways such as compelling the cRaf1MEK/MAP2 kinase cascade (mitogen-activated protein kinase 2) can also achieve this activity. HBx was first found to elevate Ras/GTP complex production, resulting in the activation of the cRaf1 signal transfer cascade. (24,25) That is why more information has been gathered to clarify the obstruction of HBx in the Ras upstream signal cascade. The other step is observing that Src is vital in HBx-forming cells. It was subsequently observed that HBx could activate the cytosolic Ca2+-dependent tyrosine kinase 2 Praline (Pyk). (27)

2.2. Human Papillomavirus (HPV)

The current data show that HPV infection and accompanying disorders are more common in developing nations. The global incidence rates of HPV in 2007, 2010, and 2019 were recorded as 10.4%, 11.7%, and 9.9%, respectively. The caseload of HPV is recorded to be highest in Asia, of which 57.7% from the Central and 44.4% from the East and South Asian subcontinent were HPV carriers. The Sub-Saharan Africa basin has an HPV caseload of 24%, of which the Eastern and Southern flanks consist of around 33% and 43% HPV woman carriers, respectively. The developed nations, mainly the European subcontinent, show a low caseload of around 4%. However, the Eastern European region shows a slightly higher caseload of HPV of around 22%. Reports suggest that females with the age group ≤ 25 years are infected by HPV prominently in the European and Asian subcontinent. Also, another study reported that females from the Eastern and Western flanks of Africa and the Central and Southern flanks of America showed higher HPV prevalence rates above the 45-year age group. Concerning the male population, HPV is sexually transmitted, and incidence rates for homosexual and HIV-positive men are higher than those for heterosexual men. The African male population constitutes the highest HPV incidence rate of around 18% per year, whereas the Asian male population presents a caseload of HPV of around 4% per year. (28,29)
The various factors such as HPV genotype, geographical conditions, population-based studies, and anatomical site sampling may impact the incidence and prevalence of these disorders. The nature portfolio states that human papillomavirus (HPV) is an infectious agent belonging to the papillomaviridae family. Its members are tropic for the skin epithelium and mucosal epithelium. More than 120 types of HPV are there, and HPV16 and HPV18 are firmly related to cervical cancer. (30) Papillomaviruses are epitheliotropic, nonenveloped, double-stranded DNA viruses that cause infection in the mucosal and cutaneous epithelia in a species-specific way in a wide range of higher vertebrates and cause distortion of cellular metabolism leading to proliferation. It comprises various viruses that are capable of infecting animals and humans. Its emergence seems to come from the conversion in the epithelium of the ancestral host, as the initial reptiles appeared about 350 million years back. With the evolving time, they got advanced with their specific hosts, having almost no cross-species shift. They are now found in birds, mammals, marsupials, and reptiles, except amphibians or lower phylogenetic orders. (31)
The transmission of HPV is carried out sexually, but it has no penetration requirement. Genital skin contact is a conventional way of transmission. There are different types of HPV, many of which are harmless. The infection generally clears without any interference after a few months. It is the most common viral infection of the reproductive region. Most sexually active women and men get infected at some point, and some might get repeated infections. The climax time of the infection is soon after sexual activity. A small number of infections within a certain category of HPV can continue and turn into cervical malignancy. In terms of HPV-linked infections, the most common is cervical cancer. Certain HPV infections can cause carcinoma of the anus, oropharynx, vagina, vulva, and penis, which can be prevented by early treatment strategies.
The noncancerous group of papillomavirus (especially categories 6 and 11) can potentially cause genital warts and respiratory papillomatosis (a medical condition in which tumors grow in the airways that enter the lungs from the mouth and nose). Despite rarely leading to fatality, they can give rise to serious illnesses like condylomata acuminata, a very usual and highly contagious infection that can affect sexual life. (32) Papillomavirus fragments have a common unenveloped icosahedral formation (50–60 nm in diameter), and its genome contains a double-stranded loop (episome) of approximately 8000 base pairs, containing 8 or 9 ORFs. Although the number of genes are limited and has a small genome size, the amount of ciphered proteins is much higher because gene expression requires various promoters and composite splicing patterns. (33) The fine arrangements show (34) that the virus coat contains 360 L1 protein molecules in 72 capsomeres. Each capsomere comprises five L1 molecules with a β-jellyroll nucleus similar to other icosahedral viruses. (35)
The interactions between the capsomeres require Late 1 protein, which stretches outward to the neighboring capsomeres and connects at their base by disulfide bridges. (36) HPV also contains an irregular number of L2 molecules, besides the N-terminal 120 amino acids, which are not entirely uncovered on the virion surface. (37) At the time of infection, L2 can bind to the extracellular fluid matrix and is separated by furin during infection. (38) The surface of the L1 area, which is exposed, mainly contains a chain of the hypervariable amino acid coil, which differentiates between various kinds of papillomaviruses in feedback for selective immune constraint from the host. Antibodies against one kind of HPV have a small binding to distant types, and this has pragmatic implications for recent preventive vaccines that provide restricted cross-protection.
The viral genome also enciphers regulatory proteins that activate cell cycle entry and cell propagation, the proteins that moderate replication of the viral genome, virus association, and possibly influential virus discharge and escalation. Despite numerous genes being involved in a virus’s premature regions, the L2 gene out-turns, having an early key role in the transmission of the viral genome into the cell and playing a part in coordinating proper genomic loading (along with E2). (39) The orderly expression of viral gene output that produces viral particles is altered in HPV-associated neoplasia. (40) In cervix diseases, the expression levels of E6 and E7 are believed to increase from CIN1 to CIN3. Shifting the expression of these genes is the basis for different tumor phenotypes. CIN1 lesions generally support the full life cycle of HPV. (41) It is believed that the increased activity of E6 and E7 occurs in high-threat HPV infections and is found to be the basis for the CIN2+ organization (phenotype), making cells prone to accumulating genetic errors, ultimately leading to cancer. (42) Although many mechanisms will influence the persistence of HPV infection, the E6 and E7 proteins are essential and adequate for HPV-mediated tumorigenesis. In all human papillomavirus cases, the E6 and E7 proteins interact with many cellular proteins, and it is not easy to distinguish the definite reciprocal action that makes the E6 or E7 proteins carcinogenic. (2,43) All papillomaviruses drive cell growth in the top layer of the epithelium to encourage the amplification of viral DNA. Yet, malignant HPV promotes cell cycle access and inactivates cell cycle barriers in the bottom layer of the affected epithelium. (44) Compared to terminally superior differentiated cells, the emerging genetic instability in these growing cells has more serious repercussions. The essential functioning of HPV oncogenes is immunity-shifting, E7-interceding degeneration of pRB group members, E6-mediated degeneration of PDZ and p53 binding domain proteins, and telomerase-mediated elevation by E6. (2,43) In contrast, β-HPV proteins E6 and E7 act as cofactors by inhibiting UV-induced DNA impaired repair and cell cycle arrest (45) but are unnecessary to maintain tumor phenotype.

2.3. Kaposi-Sarcoma Associated Herpesvirus (KSHV)/Human Herpesvirus-8 (HHV-8)

KSHV became one of the well-recognized carcinogenic infectious agents in humans identified by the International Agency for Research on Cancer (IARC) after epidemiological and molecular investigations showed the link between KSHV and Kaposi sarcoma. (46) HHV-8 viral strains are divided into A, B, C, D, E, and, most recently, N subtypes. The HHV-8 caseload in European countries is influenced by the A and C subtypes, and the B subtype influences African nations. HHV-8 D subtype influences populations belonging to Polynesian and Australian origins. Most recently, the N subtype has been identified as an HHV-8 influencer in the South African subcontinent. (47)
The human herpesvirus-8, or Kaposi’s sarcoma herpesvirus, resides in the DNA herpes virus family. (48) Gamma herpesviruses are lymphotropic viruses that typically replicate in epithelial cells, such as blood vessels, organs, and skin. These viruses can set up a quiescent state for life in the host cell. When HHV-8 enters the incubation period in the vascular endothelium and B lymphocytes, it will experience a duration of lysis and replication intermittently, mainly under favorable conditions such as immunodeficiency, malnutrition, and solid organ transplantation. It can cause Kaposi’s sarcoma (a malignant vascular condition) and B-cell lymphoproliferative diseases like Multicentric Castleman disease (MCD) and primary exudative lymphoma (PEL). Although these tumors can happen without HIV coinfection, there is a possibility that people with the infection of HIV are significantly more probable to spread HHV-8-related malignancies. In rare instances, Kaposi sarcoma is detected in patients without AIDS and is generally found in elderly Mediterranean men or induced immunosuppressed patients, including transplant populations. (3,9,49)
KSHV is a large enveloped extended, double-stranded DNA virus and belongs to the subfamily of gamma herpesvirus and genus-rhadinovirus. It has an icosahedral capsid and an outer skin containing protein and RNA. It produces various proteins that validate the virus to conceal host immunity, replicate in the nucleus, and have a potent carcinogenic response. These proteins interact with several metabolic pathways in the cell, along with NF-kB (nuclear factor kappa-B), PI3K (phosphoinositide 3-kinase), RTA (replication and transcription activator), JAK/STAT (Janus signal/kinase transduction and transcription activator), and also MAPK (mitochondrial activated protein kinase). One of the most expressed proteins is the incubation period accessory nuclear antigen 1 (LANA), which is essential for the incubation period and tumorigenesis. Furthermore, cyclins of the virus have been noted to impede tumor suppressor genes (p53 and RB (retinoblastoma)) to hinder apoptosis by regulating the cell cycle. (3,50,51)
Regardless of the analogy between the viruses and their related tumors, the specific operation and activities of proteins related to virology and tumor-related aspects seem quite divergent. These proteins are believed to play a crucial role in virus biology and are mainly associated with the pathogenesis of viruses. (52) The discovery of the vCCL 1–3, a viral chemokine, and the evidence of its pro-angiogenic activity in probing structure indicates its presumed role in immune elusion throughout the production of HHV-8, and these proteins can also cause diseases. (53) The VGPCR and homologous of the chemokine receptor can be promoted to uphold the propagation of Kaposi sarcoma lesions and are found to induce suspected types of angiogenic cell cytokines. (54) The ORF of HHV-8 K1 encodes the constructively active membrane receptors, along with K15. (55,56) Although v-cytokines, K1, and VGPCR are expressed primarily or only during generative lytic replication, any contribution to oncogenic pathogenesis may be conciliated by paracrine signals. (57)
There is a piece of ample information suggesting that cytokine-mediated paracrine signal transmission plays a part in Kaposi Sarcoma and B cell proliferation, which can be affected through this pathway. HHV-8 specifies many proteins that were not found previously in gamma herpes viruses. In addition to the possible aspect of these viral proteins in the etiology of HHV-8, the role of some of these ″unique″ viral products in viral mechanisms has only recently received attention. (52) Classical oncogenes and tumor suppressor activity are mediated by autocrine genes, and viral genes expressed in the latent period act as potential factors for malignancy. Among them, HHV-8 is primarily delayed nuclear-related antigen LANA, which describes the necessary replication and genetic makeup separation activities in splitting cells. It affects various host pathways to aid cell existence and growth. These activities are related to malignant transformation. (58)

2.4. Epstein–Barr Virus (EBV)/Human Herpes Virus 4 (HHV-4)

EBV strains exist in Type 1 and 2 forms, exhibiting varied occurrences throughout the globe. China and most European, American, and South Asian countries exhibit a higher prevalence of Type 1 EBV. Parts of the African subcontinent are prominent in prevalence rates concerning Type 2 EBV. In the case of head and neck squamous cell carcinoma (HNSCC), a coinfection pattern of EBV and HPV is observed. Biological testing in Taiwan and Morocco reported that the coinfected viral load for EPV/HPV in HNSCC stands at 48%. Similarly, testing carried out in Japan reported around 22% for the coinfected viral load, wherein no such viral load was observed in testing carried out in Greece and Denmark. (59)
Moreover, new insights into the mechanisms of EBV-infected cells’ malignant transformation, including somatic mutations and epigenetic modifications, their impact on the microenvironment, and the outcome of individual immune signatures related to the functional status of the immune system and the immune escaping approaches have been reported in recent years. The Epstein–Barr virus or Human Herpesvirus 4, which falls under the Gamma herpes virus, is an extended double-stranded DNA herpes virus with a length of approximately 172 kb. (60) EBV spreads widely via close contact between asymptomatic EBV-infected and susceptible people who excrete the virus and are found frequently among adolescents and young adults. (61) On the statistical scale, by the age of 5, antibodies against this virus have been found in approximately 50% of the population, and about 12% are vulnerable to adults who will develop antibodies in protection against the virus; half of the adults will thrive with mononucleosis disease. (62) The EBV uses a dual strategy to ensure that many cells are infected to maintain the incubation period in the body.
On the contrary, viruses can propel infected cells into the cell cycle and proliferate, significantly increasing the number of cells carrying viral genomes. The virus replicates and releases infectious virus particles and can trigger a new round of infection. Therefore, the life cycle of a virus consists of at least three stages: i) the amplification of the infected cells that maintain the viral genome in a free state, ii) the establishment of the incubation period in the organism, and iii) the reactivation, replication, and synthesis of viral offspring. The incubation period of EBV (the time between the early infection and the onset of manifestation of symptoms) is unusually extended. It generally takes 4 to 7 weeks for the symptoms to appear. (63) The most common sign of primary EBV infection is acute infectious mononucleosis, an auto-limiting clinical syndrome commonly affecting adolescents and young adults. Typical symptoms include malaise, fever, sore throat, fatigue, and systemic adenopathy. (64)
B-cell lymphoproliferative diseases that are closely related to EBV include Burkitt’s lymphoma (BL), (65) Hodgkin’s lymphoma (HL), (66) and post-transplant lymphoproliferative disease (PTLD). (67) Many T-cell lymphoproliferative illnesses have been linked to the Epstein–Barr virus. These include cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma, NK/T cell extranodal sinus lymphoma, invasive leukemia/NK cell lymphoma, and peripheral T-cell lymphoma. (67,68) Gastric cancer and nasopharyngeal malignancy are two examples of epithelial malignancies linked to EBV. (69) Following the entry into B cells, viral DNA undergoes circularization by joining terminal repeats before being nucleosomalized, structured, and packed into micro-chromosomal structures known as episomes. Regulation of the switch from cleavage to possible replication requires post-translational changes in episomes. EBV latency schemes, namely, latency 1st, 2nd, and 3rd, have been established based on the latency gene articulation pattern in general B cells. Latency gene articulation is not restricted to the latent phase 3rd, only viable in an immunosuppressive state because the latent proteins are known to be highly immunogenic. Delay 2nd latency is limited to EBER, EBNA-1, and LMP. (70) Finally, according to the distinct phases of the cell cycle, there is no gene product expression in incubation period zero, or only EBNA-1 is indicated in the incubation period 1st. (71) Latent phase 3rd tumors develop under situations of disabled T cell immunity, like the infection of HIV or a transplantation-associated state of immunosuppression. (70) EBV-linked giant B-cell and immunoblastic lymphomas frequently replace the incubation span program 3rd, independent of host immune activity. (72) In latency 2nd tumors, like nasopharyngeal tumefaction, NK/T cell lymphoma, and Hodgkin’s lymphoma, LMP1-mediated activation of the JAK/STAT and PI3K/AKT pathways have been inspected as main carcinogenic events. (70) Finally, it is to be resolute whether EBV is the motivating force for the incubation period of 1st tumors (like Burkitt Lymphoma). Most EBV-instigated tumor transformation mechanisms need several latent proteins, but EBNA-1 is generally considered the only viral protein expressed in the latent phase of 1st cancer. (73)
EBV plays a supporting part in Burkitt lymphoma because of the integral activation of a major carcinogenic event c-myc; in all BL cases, EBV states. (74) In the contrary, several reports have concluded that a small segment of these tumors have an extensive gene expression outline compared to those previously known, supporting the Epstein–Barr virus as a reason for incubation phase 1st carcinoma. The main oncogenic protein of EBV is commonly considered to be the LMP1 and is crucial for transforming reclining primary B cells into growing lymphoblasts. (70) LMP1 is a transmembrane protein that functions as a fundamental initiating CD40 receptor, which leads through the signaling pathways via downstream stimulation and participates in the differentiation of memory B cells and antiapoptotic protein expression. (70) The NF-κB, PI3K/AKT, MAPK/ERK, Notch, and JAK/STAT are the downstream signaling pathways important in the oncogenesis induced by EBV. (75) JAK/STAT and PI3K/AKT pathways are imperative in EBV-induced carcinogenesis. (68,70) The incitement of the pathways PI3K/AKT and JAK/STAT contributes to the attributes of cancer, such as the elevated antiapoptosis, genomic vulnerability, unlimited replication potential, reorganization of intensive metabolism, and inflammation promotion of tumor, metastasis, and tissue seizure. (76)
Moreover, LMP1 induces genome disequilibrium by impeding DNA repair mechanisms and inhibiting DNA impairment checkpoints. (68) The only viral protein expressed in all EBV-related malignancies is EBNA1, but the recognition of its character in carcinogenesis is limited. EBNA1 is essential for replicating and maintaining the EBV genome and can be used as an oncogene. (60) A protein is involved in tumor suppression and regulates p53 activation of PML (Promyelocytic leukemia). (77) If PML inhibits its activity, EBNA1 hinders p53-dependent p21 stimulation and apoptotic signaling, thereby improving cell survival in the case of DNA scarring. (71,77) In addition, EBNA1 can prevent cell apoptosis by negatively regulating the expression of the oncogene Myc and intensifying the expression of antiapoptotic proteins such as Bcl2 and survivin. (68)
Furthermore, information about the induction of genomic instability is linked to the EBNA1. (71) It also activates the production of reactive oxygen species (ROS), leading to chromosomal divergence. It is hypothesized that NOX2 is upregulated by EBNA, of which NADPH oxidase is the catalytic subunit, involved in the assemblage of subsequent chromosomal aberrations and ROS, telomere abnormalities, and DNA damage. (71) EBNA2 is significant for preventing the apoptosis of transformed B cells and generating transformed B cells. EBNA2 cooperates with EBNALP and is responsible directly for initiating several viruses’ transcription (LMP1, LMP2A) and proteins of cells (CD21, CD23, MYC) that are important for B cell transformation and immortalization. (70) Finally, the role of EBNA3 is to prevent the aggregation of CDK (cyclin-dependent kinase) inhibitors, deteriorate the protein RB (a tumor suppressor), balance the oncogene c-myc, and inhibit pro-apoptotic proteins. (78) The cells which are EBV-infected express large amounts of RNA transcripts of the virus, called EBERs, which have exhibited to alter various processes at a cellular level, including growth factor production, cell proliferation, apoptosis, and signal transduction. (77) EBER can alter miRNA expression to inhibit E-cadherin, leading to epithelial-mesenchymal transitions (EMT). (79) EBERs assist chemoresistance by stimulating the STAT3/IL6 signaling pathway to down-regulate the cell cycle’s inhibitors of p21 and p27 expression. (80) They also stimulate cell migration by activating pro-metastatic molecules pPAK1 and pFAK, inhibiting antimetastatic RhoGD1 fragments and KAI1. (77) EBER protects cells from apoptosis mediated by IRF3 and NF-κB signaling and inhibits IFNα-mediated apoptosis resulting in the induction of growth-promoting cytokines such as IL6, IL9, IL10, and IGF1. (68)

2.5. Merkel Cell Polyomavirus (MCPyV)

MCC instances are uncommon, but their prevalence has risen in the previous two decades and is expected to rise even more. The disease rate for MCPyV in the European subcontinent of Scotland and France was recorded to be 0.13% per 100,000 individuals, and for Australia recorded at 1.6% per 100,000 individuals. Medical survey reports in the US recorded that the case rate was standing at 2500 cases yearly. (89)
MCC has a high fatality rate, with five-year overall survival rates of roughly 51% for patients with local disease at diagnosis and inadequate prognoses for those with more advanced stages. The MCPyV is a double-stranded nonenveloped DNA virus. It belongs to the family Polyomaviridae, Orthopolyomavirus, and different species of HPyV (human polyomavirus), such as BKPyV (polyomavirus BK) and JCPyV (JC polyomavirus). Its genome size is approximately 5.4 kb, divided into regions, i.e., early and late, by the specific regions known as the noncoding control region (NCCR). Three proteins are encoded by the early region: small T (sTag), large T antigen (LTag), and 57 kT (57 k Tag). Due to splicing alternatively, 78 amino acid sequences are shared by these antigens at their N-terminus, including the epitope of the B cell. (90) This has also been observed in BKPyV; (91) the expression of sT contributes to the production of antibodies against LTag, and this event should be noted. In MCC cells, insertions, deletions, and mutations can result in shortened LTag proteins within the Tag gene and Tag proteins of 57k. The late region encodes three capsid proteins (VP1, VP2, and VP3). In mammalian or insect cells, when expressed, the protein VP1 or (VP2 + VP1 protein) self-assembles within virus-like (VLPs) particles with a 45–55 nm diameter for serological tests. (92,93) A very common viral skin infection, MCC (Merkel Cell Carcinoma), can cause unusual tumors because of the loss of immune surveillance. In addition to virus combination, LTag elimination, deletion of antigen T replication ability, and mutations of antigen T expression, MCC cell survival requires high antigen major capsid protein. (94) MCC is generally seen as asymptomatic, with erythema, plaques, or violet masses, most commonly on smooth skin surfaces and sometimes telangiectasias. It is usually located in areas exposed to the sun, typically on the neck and head, followed by the trunk and limbs, but can affect any body part, including mucous membranes. (95) The skin areas (lips, nipples, ruffles, and genital skin) mainly contain Merkel cells that are not particularly susceptible to MCC, and the source of MCC concern can be raised. In the case of MCPyV-positive, MCCs are not likely to have particular clinical characteristics; it is occasionally suggested that it is more often found in women and is confined to the limbs compared to the MCCs, which are MCPyV-negative. (96) The related disease is present in the limbs at a rate of 66%, followed by disease of lymph nodes at 27%, and 7% of distant metastatic diseases are found. (97) MCC can also be revealed by lymph nodes of unknown origin or distant metastasis, and there is no primary MCC in the skin or mucous membranes diagnosis. (98)
Recent studies on MCPyV have centered on the role of the virus’s encoded protein in tumorigenesis. Six out of eleven samples of MCC tumors were discovered to have MCPyV DNA integrated with them. The team quickly realized that viral DNA could be monoclonal integrated into the cell’s MCC genome by comparing the MCPyV DNA sequences in isolated metastatic tumors from different patients, suggesting that they occurred in cancer cells in the initial stage of the integration event before clonal expansion and tumor development. (99) This early observation shows that the integration of the virus is a key occurrence in MCPyV-driven MCC oncogenesis in many other oncogenic viruses. Follow-up studies by various groups have affirmed that the genome of MCPyV is cloned and merged into the cancer genome in at least 80% of cases of MCC. (100−102) Like other polyomaviruses, MCPyV LT has the conserved domains necessary to control the host cell cycle and replicate the viral genome. N-terminal LT comprises the DNAJ domain that binds to heat stroke protein, the motif protein binding the LxCxE (RB) of retinoblastoma tumor suppressor, and the conserved region 1 (CR1), which acts like the transformation of a cell area of the adenovirus E1A protein. (90) The OBD (Ori binding domain) and the helicase/ATPase domain (103,104) are located in the C-terminal region of LT and are essential for inducing viral DNA replication. Examining MCC tumors for LT transcripts expressed by the MCPyV incorporated into the genome. (90) It was found that tumor-derived mutant LT truncation (LTt) sequence has mutations or premature stop codon deletions, which are the Ori Binding Domain C-terminal and domains of helicase required for dynamic viral replication, as to retain the binding motif of RB and the LT N items of other functional domains. Since the integrated virus is incompatible with viral DNA replication, it may inhibit tumor suppressor protein RB and control the host’s cell cycle. By contrast, similar LT mutational features were absent in MCPyV DNA obtained from a nontumor source. (90) The sT and LT proteins are similar because they both include DNAJ and CR1 domains, but sT’s C-terminus is unique because it contains two protein phosphatase 2A (PP2A) binding motifs. MCPyV genome integration with MCC generally results in unaltered expression of the native sT antigen. (90,105) Tumor regression in vivo was achieved with short hairpin RNA-mediated elimination of MCPyV sT/LT antigen in MCC cell lines. (105,106) These studies demonstrate that MCC tumor cell growth in vitro and in xenograft models requires the expression of MCPyV LT and sT antigens. These innovative studies support the idea that MCPyV is harmful to the tumorigenic development of most MCC cancers. (105,106) Two distinct MCPyV mutagenesis processes, namely, monoclonal coalescence of the virus’s DNA into the host genome and tumor-specific single MCPyV LT bridging, are required for initiating MCPyV-positive MCC tumor formation. The viral genome’s continuous replication state, exacerbated by the suppressive action of RB, may allow for the acquisition and accumulation of the essential genetic alterations by newly forming tumor cells as they increase, allowing them to progress to the MCC stage. The inactivation of RB is a crucial step in the occurrence of MCC tumors. Although most negative-MCPyV MCCs transfer gene mutations/deletions deactivate the cell’s RB1 gene, (107−109) positive MCPyV MCCs usually encode the wild-type gene RB1. (65,108) However, all familiar MCC-derived LTt mutant truncation retains the RB motif binding, (90) allowing binding of them to the factors of tumor suppressor with higher affinity. (110,111) These examinations specify that the interaction between the RB and MCPyV may be essential in promoting the malignant progression of positive-MCPyV tumors. Integration of proviruses like MCPyV into oncogenic MCC cells that generate LT truncation mutants usually results in losing the DDR activation domain. (90) C-terminal LT truncation mutant is more potent in encouraging cell growth than full-length LT protein. (112) This suggests that virus-induced host DDR may be a barrier to malignant development. Therefore, in MCPyV-driven tumorigenic development, releasing the tumor brake of a suppressor can remove the innate DDR-inducing and growth-inhibiting activity of the domain C-terminal of MCPyV LT, allowing tumor growth. (113)
It is worth mentioning here that MCPyV diverges significantly from other polyomaviruses. MCPyV sT, in contrast to sT from other polyomaviruses, plays an active role in the virus’s ability to modify host cells. sT is more commonly found than LT antigen in MCPyV-positive MCC tumors and is present in most MCC tumors. (114) In MCC cells, overexpression of LTt does not fully restore growth inhibition when MCPyV LTt and sT are removed. (106) These findings suggest a critical function for sT in MCPyV-related tumor progression. A sustained expansion of MCC cell lines that test positive for MCPyV requires the expression of sT. The expression of sT alone is sufficient to convert rodent fibroblasts in the non-anchored lesion development assay. Hyperphosphorylation of eukaryotic initiation factor 4E binding protein 1, a critical downstream target of the PI3K/mTOR/AKT signaling cascade, leads to the overactivated cap and, hence, sT’s transformation potential. mRNA is required for cell translation. (114) Inhibition of PP2A’s ability to stimulate cell proliferation is one-way. The other way can affect the AKT signaling pathway. (115) Despite MCPyV sT’s ability to bind PP2A, it does not appear that PP2A inhibition is necessary for transformation activity. (114,116) Traditionally, Merkel cells tend to produce MCC because the neurosecretory granules in the tumors indicate the origin of the neural crest (117) and also express the unique Merkel cell marker, cytokeratin 20. (117) It is suggested that tumors of MCC may originate from the lineage of B cells because they are willing to express pro/pre-B markers of cells. (118) Since most dermal MCC cancers start in skin fibroblasts, the discovery that MCPyV may infect these cells is consistent with this. (119) There is evidence that MCPyV infection of skin fibroblasts can drive their transformation into other cell types (such as B cells, skin cells, and Merkel cells) under as-yet-unknown circumstances. New evidence suggests that skin fibroblasts may be able to undergo a self-renewal process and transform into MCC cells by expressing the MCPyV LTt. MCC cells are characterized by a neuroendocrine-like development pattern. (120) On the other hand, Merkel cell precursor virus (MCPyV) actively replicates in dermal fibroblasts and may accidentally reach the precursor cells of neighboring Merkel cells. (121) This uncontrolled propagation environment can promote cancer when these cells differentiate into Merkel cells and the replication of defective MCPyV genome integrates into the host cell genome. These two ideas, MCC arising from dermal fibroblasts and MCPyV infection via nonproductive transient Merkel cells, will need to be tested once an in vivo infection model of MCPyV is available. (121)

2.6. Hepatitis C Virus (HCV)

Liver cancer is the sixth most prevalent cancer worldwide and the fourth main cause of cancer death. A record population of more than 150 million people were diagnosed with chronic HCV in 2005. The caseload of HCV ranges from 4 to 16% in Asian and African inhabitants, with a ≥ 20-year band gap population covering around 4% of the total caseload. The strait of Taiwan is reported to have the highest incidence rate of HCV cases. The developed nations of North America, the western and northern subcontinents of Europe, and Australia are geographic zones with a low frequency of HCV infection. Some developed regions with relatively minimal HCV rates include Germany recording 0.6%; Canada recording 0.8%; Australia and France recording 1.1% seropositivity levels. The HCV seropositivity levels in the US were 1.8%, Japan with around 1–3% seropositivity levels, and Italy recorded 2.2% seropositivity levels. (122,123) Hepatocellular carcinoma (HCC) is the most common liver cancer, accounting for 70–80% of cases. Chronic infection with the hepatitis C virus (HCV) has been identified as a key driver of HCC. (124) According to mounting evidence, hepatocarcinogenesis is linked not only to inflammation and consequent fibrosis but also to HCV. It has been demonstrated in experiments employing transgenic mice and cell-culture models in which HCV proteins are produced. (125) The Hepatitis C virus is an enveloped compact RNA virus that belongs to the family Flaviviridae and the Hepacivirus genus. HCV RNA genome is single-stranded with positive polarity, surrounded by a core protein and a bilayer of lipids that consists of two viral glycoproteins (E1 and E2) to form virus particles. (126) Although there are differences in nucleotide sequence between the genetic constitution, all currently identified Hepatitis C virus genotypes are pathogenic and hepatotropic. (127)
Hepatitis C spreads through the blood contact of a diseased person. Nowadays, most people get infected with HCV by sharing syringes or other equipment to prepare and inject drugs. For a few people, hepatitis C is a limited condition illness. Still, for more individuals who get infected with the hepatitis C virus, it can turn into a deep-rooted chronic infection. Hepatitis C, which is chronic, can cause consequential and even lethal health problems such as liver cancer and liver cirrhosis. People with chronic hepatitis C generally have no symptoms or discomfort. When the appearance of symptoms takes place, those are usually signs of the advanced stages of liver infection. There is no vaccination available against hepatitis C. The best method to block hepatitis C is to avoid behavior that can spread the disease, especially by injecting drugs. Diagnosis for hepatitis C becomes crucial because treatment can cure most patients with the infection within 8 to 12 weeks. (128)
The life cycle of HCV initiates with the binding of virus particles to distinct receptors on liver cells. (129) So far, class B class I HDL receptor scavenger receptor, CD81 four-span membrane protein, claudin1 tight binding protein, and occludin are known cell receptors that can initiate the binding phase infection of HCV. It is suggested that the virus is internalized after it is bound to its receptor complex and the nucleocapsid is released into the cytoplasm. Then, the virus evolves to release its genomic RNA, which is used for polyprotein translation and replication in the cytoplasm. Replication of the hepatitis C virus occurs in a ″replication complex″ containing nonstructural proteins of the virus and cellular proteins. (130) Also, the HCV replication is catalyzed by the NS5B protein. However, there are essential viral proteins that are found to be nonstructural. The helicase/NTPase domain of protein NS3 has a variety of significant functions for virus replication, including the RNA-activated action of NTPase, RNA binding, and unwinding of RNA regions with a considerable secondary structure.
The formation of a replication complex is initiated by NS4B, which supports the replication of HCV. The protein NS5A also plays a crucial regulatory role in virus replication. New antiviral drugs that are direct-acting (DAA) are now on the market, particularly designed to hinder RNA NS5B-dependent RNA polymerase enzyme. Several newer DAAs (such as protein NS5A inhibitors) have also shown promising results in clinical studies. (131,132) In HCV replication, many cytokines are involved, such as cyclophilin A, which is necessary for the replication of HCV by interacting with NS5B and NS5A, and microRNA122, which assists by binding to the 5′ untranslated domain (5′UTR) of HCV, and then the genome replicates. Therefore, factors of the host can also become potent targets for the therapy of anti-HCV. According to a recent study, at least two targeting agents of the host (HT) have clinically reached the stage of development, including microRNA122 antagonists and cyclophilin A inhibitors. (131,133,134)
The mechanism involved is appropriate low-density lipoprotein synthesis/secretion in the production of infectious fragments of HCV. The Hepatitis C virus uses this lipoprotein biosynthetic pathway to generate mature particles of the virus and exports them. (132,135) Growth factors such as EGF (epidermal growth factor), FGF (fibroblast growth factor), HGF (hepatocyte growth factor), and IGF (insulin growth factor) trigger downstream signal transduction by binding to their specific tyrosine kinase receptors. (136) The cascade of occurrence after the EGFR (epidermal growth factor receptor) is the signal transduction pathway studied most widely. (137−139) ErbB1 and the other three analogous members of the family EGFR (ErbB2, ErbB3, ErbB4) modulate cell differentiation, proliferation, and migration under normal physiological state. (138) EGFR is essential for epithelial development, and other family members are essential in breast, heart, and nervous system development and diseases. (137,140,141) The EGFR also plays a key role in developing embryo and stem cell regeneration into the skin, liver, and intestines. (142) In addition, the EGFR has also attracted much focus as a determinant risk of cancer and progression. (143,144) Viruses have established complex methods to manipulate the function of EGFR (i.e., disrupt EGFR expression, activity, or recycling). (145) The host factor for HCV is EGFR, by regulating complex coreceptor assembly to enter hepatocytes, (146,147) viral internalization, (148) and membrane fusion. (146) In addition, the signaling pathway EGFR maintains phosphorylation of the signal transducer and activator of transcription 3 (STAT3) by hindering negative feedback regulators (i.e., the cytokine suppressor 3 signaling, SOCS3), thus regulating the effect.
(146) HCV is important for controlling the signaling of EGFR. Indeed, the hepatitis C virus involves the signal transduction of EGFR and actively induces activation of this pathway during HCV binding and infection (149,150) and prolongs EGFR signal transduction by interrupting the degradation of EGFR through NS5A, as described by its ectopic expression. (151) This can result in an increased threat of HCC in infected patients because continuous signaling of EGFR is a leading factor in hepatic disease. (143) The transforming growth factor-β (TGFβ) of cytokine dimers of the superfamily with a pleiotropic and conserved structure. Under physiological conditions, TGFβ acts as an effective growth inhibitor for various cell types; (152,153) and promotes epithelial cell apoptosis (154) (Figure 2). Thus, damaged TGFβ can lead to excessive cell proliferation and cancer. (155)

Figure 2

Figure 2. Pro-oncogenic inflammatory microenvironment induced by HCV. HCV infection in hepatocytes is detected by viral sensors, such as RIG-I and TLR3, leading to the production of type I IFNs. As with most viruses, HCV has developed various strategies to dampen this antiviral response. The persistent inflammatory environment in the liver, combined with the action of viral proteins, establishes a sustained activation of signaling pathways associated with cell survival (e.g., STAT3, AKT, NF-κB, and FasR). Sensing HCV-infected hepatocytes by macrophages triggers NLRP3 inflammasomes, inducing the secretion of IL-18, which activates NK cells. Moreover, IL-1b and IL-6 produced by macrophages favor the activation of HSCs which are central components in the progressive deposition of collagen associated with liver cirrhosis. STAT3 also plays a role in developing MDSCs, which produce IL-10 and favor the expansion of regulatory T cells. This altered immune response is further accentuated by the increased expression of PD-1 and FasL, impairing cytotoxic T lymphocyte function and inducing their apoptosis (adapted with permission under a creative commons (CC-BY 4.0) from ref (124)). Copyright [2020] [MDPI].

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Furthermore, these cytokines stimulate the expression of extracellular matrix components and build up fibrosis in different tissues in vivo. (154) In the case of the liver, TGFβ appears to contribute to all phases of disease development, from early damage to inflammation and fibrosis, through cirrhosis and HCC. (156,157) In early cancer development, TGFβ may act as a tumor suppressor. Still, once tumor cells become resistant to its suppressive properties, it will promote tumor progression, migration, and invasion in advanced HCC. (156,158)
The key effector of intracellular signal transduction is Smad4. Like TGFβ, it has duplex tumor suppressor and HCC promoter roles. (159) In the nucleus, the transcription of target genes is regulated by the SMAD complex induced by TGFβ and the necessary cofactors involved in transcription. Genetic characteristics are specifically induced by the SMAD complex through the typical TGFβ signaling pathway, (160) causing growth arrest and pro-apoptotic indication in the early stage. Later, generative and antiapoptotic feedback gain advantages through crosstalk with growth signals. This nonclassical TGFβ pathway includes regulating EGFR by small GTPase signaling pathways, MAPK (mitochondrial activated protein kinase), PI3K (phosphoinositide 3-kinase)/Akt, Ras, and Rho-like. (161,162) TGFβ can induce EMT in primary hepatocytes of humans, which is a procedure that stimulates metastasis and cell invasion. (163) Epithelial cells lose their phenotypic attributes and gain invasiveness during TMS, becoming cells of mesenchymal. EMT is necessary physiologically for embryonic development. However, there is an escalating affirmation that it also plays a role in pathological conditions and may contribute to the development of metastatic oncogenesis. (164) A captivating hypothesis suggests that chronic infection causes HCV selection for protumorigenic mutations in the liver, which strongly interferes with TGFβ signaling. Core variants from HCC support the isolation of HCV. Compared with hepatitis C virus core forms isolated from adjacent tumor tissues, HCV core variants can better resist TGFβ-mediated antiproliferation effects and promote cell transformation. (165) Its association with SMAD and a core expression of HCV on the surface of infected liver cells activate endoglin’s expression (CD105). As a constituent of the TGFβ complex receptor, abundant endoglin triggers fiber production and promotes the growth of tumors and metastasis. (166) Endoglin induces the inhibitory function of DNA binding 1 (ID1) by stimulating ALK1/SMAD1/5 signaling, which plays a role in proliferation and antiapoptosis. It is a primary regulator of CSC maturation. (167) Infection of HCV or ectopic articulation of the viral core elevates the expression of ID1-associated CSC, proliferation, and survival markers (i.e., NOTCH1, BCL2, HES1, CyclinD1, NANOG, and SOX2 proteins). (166)
Furthermore, endoglin is a marker of angiogenesis in patients with HCC. (168) The Hedgehog (Hh) pathway coordinates key morphogenesis operations, including propagation, survival, migration, and differentiation. (169) Hedgehog ligands are necessary during embryogenesis and morphogenesis and for maintaining stem cell homeostasis in adulthood. Importantly, the Hh pathway plays an essential role in hepatic repair and regeneration in adults (170) and is associated with many types of liver malignancy, such as cancer of the gallbladder, cholangiocarcinoma, (171−173) hepatoblastoma, (172) and HCC (174) accumulation of markers of liver damage (i.e., PDGF (platelet-derived growth factor), TGFβ, and EGF) may lead to the production of Hh ligands. (175,176) In patients with hepatitis, the Hh pathway was found to be generated (177) and may reflect the damage of tissue and regeneration of the liver during chronic infection. Strikingly, the cell’s permissibility for replication of HCV appears to be pragmatically correlated with the action of the Hh pathway, (178) indicating that regeneration of the liver and an environment of profibrosis may stimulate the infection of HCV. The recognition of other key regulators of liver regeneration initiated by HCV infection supports this, which includes signaling of EGFR (146,149,150) and IL6/STAT3. (179) Furthermore, the Hh activity promotes crosstalk between EMT and TGFβ and Wnt signals, (180) which once again highlights the correlation between the induction of EMT and hepatitis C virus and its repercussions for HCV-related hepatic pathogenesis and the progression of HCC. The summarized version of the viral strains, their genomic material, and their oncogenic property has been highlighted in Table 1.
Table 1. List of Viruses and Their Related Malignancies
S. No.VirusesGenomeTypes of CancerReferences
1.Merkel cell polyomavirus (MCPyV)Double-stranded DNA PolyomaviridaeMerkel cell carcinoma (25)
2.Hepatitis B virus (HBV)Partially double-stranded DNA HepadnaviridaeHepatocellular carcinoma (81)
3.Human Papilloma virus (HPV)Double-stranded DNA PapillomaviridaeCervical, neck, head, and anogenital tract carcinoma (82,83)
4.Kaposi sarcoma herpesvirus (KSHV/ HHV-8)Double-stranded DNA HerpesviridaePrimary effusion lymphoma, Kaposi sarcoma, multicentric Castleman disease (84)
5.Epstein–Barr virus (EBV/HHV-4)Double-stranded DNA HerpesviridaeBurkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma (85)
6.Hepatitis C virus (HCV)Single-stranded RNA FlaviviridaeHepatocellular carcinoma, Lymphomas (86)
7.Human T-cell leukemia virus- (HTLV-1)Single-stranded RNA RetroviridaeAdult T-cell leukemia and myelopathy/tropical spastic paraparesis (87)
8.Human immunodeficiency virus (HIV)Double-stranded RNA RetroviridaeElevates the immunosuppression-mediated malignancies by other oncogenic viruses (88)

2.7. Human T-cell Lymphotropic Virus (HTLV-I)

The geographic distribution of the virus has been defined. However, some puzzles persist, such as the high prevalence in southwestern Japan but the low prevalence in neighboring regions of Korea, China, and eastern Russia, and seemingly isolated pockets of infection in Iran. The seropositivity levels for HTLV1 in parts of Europe and North America were reported to be low. In the United States and Canada, seropositivity levels were recorded to be 0.01–0.03%; in Norway, 0.002% was recorded, and in Greece, 0.0056% was recorded. Higher seropositivity levels of about 10% were recorded in the Southwestern Japan flank among pregnant females and blood donor individuals. Following Japan, Caribbean countries such as Jamaica and Trinidad present around 6% seropositivity levels for HTLV1. In the Sub-Saharan Africa basin like Benin, Cameroon seropositivity levels of around 5% are reported. In parts of the Middle East like Iran and Melanesia, HTLV1 seropositivity levels were reported at ≤ 5%. In South American countries, namely Argentina, Brazil, Columbia and Peru, seropositivity for HTLV1 was recorded at around 2% specific to samples of pregnant females and native individuals. (181,182) HTLV-I is the only human pathogen of this oncogenic virus subfamily, an encapsulated single-stranded RNA virus belonging to the Retroviridae family, including HTLVII, bovine leukemia virus (BLV), simian T-cell leukemia virus (STLV), HTLV-III and HTLVIV. (183) It contains a diploid genome comprising two 9032 base pair long positive-strand RNAs. The gag, pol, and env genes are flanked by two long terminal repeats (LTR) sequences comparable to those in other retroviruses. However, between env and 3LTR, HTLV-I possesses a unique 1.6 kb region known as pX. (184) This region encodes many regulatory proteins: p40tax (Tax), p27rex, p21rex, p12, p13, and p30. The basic leucine zipper factor HTLV-I (HBZ) is encoded by the negative (complementary) strand of the pX region. (185) Among them, Tax and HBZ are related to the pathogenesis of the virus. (See ″Pathogenesis″ below). Cell entry and replication compared with HIV infection, the level of viremia in the HTLV-I infection is extremely low. The new infection results from the spread of infected lymphocytes rather than cell-free virus particles. HTLV-I is CD4 T cell-specific, although virus particles penetrate CD4 T cells more efficiently via direct cell-to-cell contact across viral synapses (186) than plasma-free virus particles (187) observed that cell-free HTLVI could infect dendritic cells (through heparan sulfate proteoglycan and neuropilin 1), which can then expand to CD4 T cells. (188) The glucose transporter GLUT1 has also been discovered as a receptor for the envelope glycoprotein HTLV-I. (189,190) GLUT1-deficient cells, on the other hand, can infect HTLV-I. (191) CD4-positive T cells infected with HTLV-I can produce CCL22, a CCR4 ligand. CCL22 attracts CD4 cells expressing CCR4, leading to preferential transmission of HTLV-I to CCR4-positive and CD4-positive T cells. (192)
Although free viral particles have been found to infect dendritic cells, HTLV1 infection occurs predominantly and most efficiently through disseminating infected lymphocytes. (193) CCL22 (a CCR4 ligand) is produced by infected CD4+ cells, which bind to CCR4 on CCR4+ CD4 cells, forming what is known as ″viral synapses.″ In study, (194) HTLV1 is more effectively spread among the CD4+ CCR4+ (TC) T cell population. Although HTLV1 and HIV may both infect TC, there are significant variations in their virology and final pathogenesis (HIV). One such distinction is this distinctive pattern of cell-to-cell communication. When compared to the high viral load of HIV, the viremia associated with HTLV1 is rather mild. High genetic stability is a second distinguishing feature of HTLV1, which is ensured by the virus’s reproduction method. (195) The DNA product of the HTLV1 genome is introduced into the host genome once the virus enters a cell and undergoes reverse transcription. The virus has two options for further replication: infectious replication, in which case reexpression of the integrated provirus will generate new intracellular viral particles, or mitotic replication, in which case the integrated provirus will reproduce itself. Viral replication is inextricably related to the reproduction of the host cell, unlike the case with independent viral DNA polymerases. (196) This results in a stable gene product (not the HIV gene product) that circumvent immunological escape by maintaining a low viral replication rate and high transcription fidelity. (197) HTLV1 can regulate its transcription, so the transient expression can help evade host immune control gene products. (198) Two regulatory proteins facilitate this: the Tax mentioned above (activation of transcription) and Rex (repression of transcription). (199) Integrating the provirus and the translation of viral products is related to cell proliferation and an increased survival rate, which confers protection against the virus. Importantly, unlike HIV, HTLV1 infection does not cause cell death. On the contrary, TC can escape apoptosis and is easily transformed. (200)
Adult T-cell leukemia/lymphoma (ATL) is etiologically linked to HTLV1. (182) HTLV1 has more intricate genetic makeup and regulation than other leukemia viruses. Besides the structural genes encoding functional viral proteins (gag, pro, pol, and env), the HTLV1 genome also includes genes encoding the nonstructural proteins Tax and HBZ, which are important in controlling the viral gene. (201) Although large advancement has been done in comprehending the complicated mechanisms of ATL due to HTLV1, research has nevertheless had to make clear the role and control of viral gene products and their interactions with each other, in addition to the interplay with cytokines. (201) Previous research showed that Tax1 is mainly located in the nucleus, especially accumulating in the mottled structure of the nucleus. Recently, it has been mentioned that Tax1 is likewise positioned within the cytoplasm, (201,202) even though the mechanism that regulates the subcellular localization of Tax1 has not at this time been explained. The N-terminal domain of Tax1 consists of a binding vicinity with CREB72, which is vital for its interplay with proteins required in cell cycle advancement, transcription, and management of cell signaling. (203) Besides, Tax1 interacts with cytokines, which include the reaction of cAMP-response element binding protein (CREB) and the transcriptional coactivator CBP/p300. (204) As a viral oncoprotein, Tax1 performs a key function in tumorigenesis. It involves ATL by regulating many intracellular signaling pathways, including the IκB kinase (IKK)/NF-κB (205) signaling pathway, DNA repair pathway, and innate immune signaling pathway. Pathogenesis includes RIGI/MDA5-dependent and TLR-independent pathways, TRIF-dependent TLR pathways, and the lately explored cGASSTING pathway. (206,207) The typical characteristics of tumor cells are genetic and phenotypic instability, called mutant phenotype. (208) Genomic harm can arise because of internal (metabolic) and outside factors (genotoxic stress) and DNA replication mistakes. (209) Generally, those errors are corrected immediately through many cellular restore mechanisms. (208) If those repair pathways are not carefully coordinated, genomic lesions can form mutations in cellular division and DNA replication, prompting genome instability. (210) It is widely believed that increased mutations in the cellular genome and the suppression of the Tax1-mediated DNA repair pathway are two hallmarks of HTLV1-transformed cells. (209) These alterations indicate the protein’s ability to inhibit DNA repair pathways such as base excision repair, nucleotide excision repair, mismatch repair, non-homologous end joining, and homology-directed repair (homologous recombination).
For the NER pathway, specifically, it has been shown that Tax1 can hinder the pathway via transactivation of PCNA (proliferating cell nuclear antigen). PCNA is essential for DNA replication and repair as it acts as a cofactor for DNA polymerase. (211) Additionally, Tax1 can impede tumor suppressor action by inactivating p53. (212) When it comes to NER, Tax1 acts in a dual dose-dependent fashion. Researchers have identified a novel open reading frame (ORF) on the HTLV1─a negative strand that encodes a basic leucine zipper factor termed HBZ. (185) Genome integrity, cell proliferation, apoptosis, autophagy, and immune evasion are only some of the cellular processes that HBZ regulates. (213) By building heterodimers with host factors such as CCAAT/alpha-enhancer binding protein (C/EBPa) and activating transcription factor 3 (ATF3), HBZ controls cell proliferation (ATF3). In many cases, C/EBPa suppresses cancer cell growth. (214) By interacting with C/EBPa and decreasing its DNA binding ability, HBZ can counteract the growth-inhibitory effects of C/EBPa and stimulate cell proliferation. There are two sides to the tumorigenic action of the HBZ-binding protein ATF3. ATF3 is a tumor suppressor because it promotes p53 signaling. (215) However, it stimulates the growth of cancer cells. (185,215) ATF3′s p53 enhancer function is negatively affected by HBZ, which is detrimental to ATL development, although ATF3′s function in cell proliferation is unaffected by HBZ in ATL cells. (215) Two investigations have demonstrated that HBZ promotes ATL cell proliferation via autocrine and paracrine mechanisms. (216) ATL cell proliferation and migration are both improved by HBZ because of its effect on the production of the noncanonical Wnt ligand Wnt5a, whereas the canonical Wnt pathway is inhibited. Furthermore, HBZ promotes ATL cell proliferation by elevating the expression of brain-derived neurotropic factor (BDNF) and its tropomyosin receptor kinase B (TrkB). (216) Double-stranded breaks (DSB) induced by HBZ are based on various microRNAs (miRNAs) that can induce HBZ, such as miR17 and miR21. (217) miR17 and miR21 target and inhibit the expression of OBFC2A. OBFC2A is a gene encoding hSSB2, and hSSB2 is a single-stranded DNA-binding protein that prevents genome instability. (217,218) Therefore, HBZ destroys the integrity of the host genome through the HBZ microRNA OBFC2A cascade. (218) Studies have shown that among the HTLV1 viral proteins, HBZ has the lowest immunogenicity because anti-HBZ antibodies are almost undetectable in individuals infected with HTLV1. (219) A recent study showed that the weak binding strength of HBZ epitopes to CTL and low expression of the HBZ protein could greatly hamper the host’s ability to successfully initiate an anti-HBZ CTL response. It has been suggested that the low immunogenicity of HBZ may help infected cells to evade immune surveillance and contribute to HTLV1-mediated tumorigenesis. (220)

2.8. HIV (Human Immunodeficiency Virus)

The human immunodeficiency virus (HIV) isolates are currently categorized into two types: HIV type 1 (HIV1) and HIV type 2 (HIV2). HIV1 is the most common cause of AIDS worldwide, while HIV2 is only found in portions of West and Central Africa. HIV belongs to the Lentivirus genus of the Retroviridae family and is genetically connected to it. Lentiviral infection usually has a chronic course, long clinical incubation, persistent virus reproduction, and central nervous system involvement. (221) The retroviral genome comprises of two identical copies of single-stranded RNA molecules, and structural genes gag, pol, and env. Although the basic structure (three structural genes, gag, pol, and env) is the same in all retroviruses, the genome structures of HIV1 and HIV2 viruses differ. The HIV1 and HIV2 genomes contain complicated combinations of other regulatory/helper genes and these three genes. Even though central nervous system disorders are more common in HIV2 infection, (222) AIDS can be caused by any of these two viruses. In addition, HIV2 seems less virulent than HIV1, and the infection process takes longer to develop into AIDS. (223) The HIV particle structure of HIV1 and HIV2 is comparable to those of other retroviruses, as seen in Figure 4.
The gag gene produces matrix proteins (p24, p7, and p6) as well as core structural proteins (p17). The viral envelope glycoproteins gp120 and gp41, which recognize cell surface receptors, are encoded by the env gene. The pol gene encodes enzymes required for viral replication. They are reverse transcriptase, which transforms viral RNA into DNA; integrase, which integrates viral DNA into host chromosomal DNA (protovirus); and virus protease, which breaks the virus’s RNA protease. The predecessors of the Gag and Pol proteins are broken down into their constituents. HIV has a particle diameter of 100 nm and is enveloped by a lipoprotein-rich membrane. A glycoprotein heterodimer complex made up of an outer surface of gp120, and a transmembrane glycoprotein trimer of gp41 is found on each viral particle membrane. Because the interaction of gp120 and gp41 is not covalent, gp120 can be lost spontaneously in the immediate environment and detected in HIV-infected patients’ serum and lymphatic tissue. The virus can also draw from diverse host cell membrane proteins, such as HLA class I and class II proteins, or adhesion proteins, such as ICAM1, during the budding process from infected cells and aids in the attachment of additional target cells. Within the viral lipoprotein membrane, matrix protein (p17) is attached. A capsid of polymers of the core antigen is included in the viral membrane and matrix protein (p24). Two copies of HIV RNA are coupled with a nucleoprotein, reverse transcriptase, integrase, and protease in the capsid. (224)
Another feature of HIV is the presence of helper/regulatory genes that regulate the virus’s replication. (225) The tat gene, for example, encodes a protein (Tat) produced shortly after infection and increases HIV gene expression. The rev gene encodes the Rev protein, which ensures that it is exported from the nucleus to the cytoplasm as properly processed messenger and genomic RNA. Other HIV helper proteins’ roles are not well understood. Vpr protein is thought to be involved in cell cycle arrest. This protein also enables the reverse transcription of DNA into the nucleus of nondividing cells (such as macrophages), a function that Vpx in HIV2 does. The vif gene encodes a small protein (Vif) that can boost the infectivity of progeny virus particles. Vpu is a protein that is important for properly releasing viral particles, and the vif gene encodes a small protein (Vif) that can enhance the infectivity of progeny virus particles. Finally, the Nef protein has a variety of activities, including cell signaling and down-regulation of the CD4 receptor on the cell surface, which allows the virus to bud late in the replication cycle. (225)
Even though there is a definite association between HIV1 infection and the development of some malignancies, it is unclear whether HIV1 acts as a carcinogen directly. Viral-induced carcinogenesis appears to depend on several conditions in the setting of HIV-1 infection, the most common of which include coinfected virus cooperation and anomalies in the immunological and nonimmune microenvironments. In this regard, we will discuss the mechanism of HIV1-associated tumorigenesis, concentrating on virus products’ direct ability to promote tumorigenesis in cells and the indirect cause of inducing cancer. As a result, significant immunological diseases develop. (226) The importance of viral cofactor cooperation in the malignant transformation of HIV1-infected persons is stressed. High immunodeficiency and chronic immune activation/inflammatory state will enhance vulnerability to infection and multiple replication pathways. (227) Since the direct and transient depletion of T cells and the microenvironmental changes that define pathogenic HIV1 infection led to the failure of immune surveillance, it makes sense that HIV1 replication derivates may also result in tumorigenesis. (228) The contribution of HIV1-induced molecular changes in the generation of tumor transformation independent of immune system abnormalities have been proven, mostly using in vitro cell line models. The direct cooperative involvement of HIV1 in mediating carcinogenesis has been established in the context of KS. The current evidence suggests that the chronic immunological inflammatory state associated with HIV1 illness contributes to B cell activation and, eventually, lymphoma; HIV1 replication products may also contribute directly to lymphoma induction. Through its association with DCSIGN, the HIV1 envelope protein gp120 can directly stimulate B cells, causing class switching and recombination of immunoglobulin genes, interleukin release, and AID-induced activation (Figure 3). (229) The interaction of HIV1 envelope interacts with a range of cellular proteins with different functions, such as adhesion molecules, MHC components, macrophages, and B and T cell surface proteins. The chemicals aid in stimulating B cells and developing lymphoma.

Figure 3

Figure 3. Schematic representation of the lymphoma microenvironment including immune components (CD4 and CDT lymphocytes, macrophages, cytokines, and chemokines) and nonimmune components (fibroblasts, stromal cells, and blood vessels). This figure includes viruses and their products influencing the microenvironment (Created in Biorender).

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Many immune cell components, such as activated T cells, B cells, and macrophages, are found in the tumor microenvironment. The role of the interaction of HIV1 with the microenvironment has been increasingly highlighted in recent years. As previously stated, HIV-1 infection can severely deplete cytokine and chemokine levels while encouraging antiviral immunity formation. However, these mediators can harm the host by restricting the establishment of a strong immune response to infection and influencing cancer development directly or indirectly. (230−232) Increased IL6, IL10, CXCL13, and TNFα are linked to an increased risk for NHL in HIV1-infected persons. (233) The activation of pro-inflammatory mediators by HIV1 infection may alter the development of other immune regulatory factors, cell proliferation, apoptosis sensitivity, and other microenvironmental physiological processes. (227) As previously discussed, the HIV1-dependent transition of T helper (h) 1 cell subsets to Th2 CD4+ is thought to be a crucial stage in immunological dysregulation. Increased Th2 differentiation could be a precursor to AIDS-related NHL and a factor in Th17 overexpression. (234)
Furthermore, Th2 or Th17 cytokines induce AID expression in the pathogenesis of AIDSNHL. (233) In HIV-1 infected patients, cytokine/chemokine system dysregulation may also induce neovascularization. In addition to Tat’s role in boosting capillary development, (235) HIV1 matrix protein p17 has been found to stimulate angiogenesis through chemokine receptor linking through various pathways. (236) In more detail, p17 is released from HIV1-infected cells and binds to CXCR1, after which CXCR1 pushes human monocytes into the microenvironment like IL8 chemokines, resulting in long-term inflammation. (237) Increased levels of IL6 and TNF in HIV1-infected individuals’ plasma can cause the production of COX2 and PGE2, which has been linked to the development of AIDS-related cervical cancer, (238) and this impact could be linked to angiogenesis. (238)
Further research is needed to determine the specific role of HIV1-driven angiogenesis in cancer formation and progression. Finally, the nonimmune microenvironment may play a role in the occurrence and progression of AIDS-related malignancies, possibly through virus-cooperative mechanisms. Endothelial cells, stromal cells, and fibroblasts comprise most of the nonimmune microenvironment in lymphoma, contributing to tumorigenicity. Research on nonimmune microenvironmental components in AIDS-related NHL is mostly focused on neovascularization, although whether HIV1 can alter this process by productive infection of endothelial cells is still debated. (227) Although aberrant neovascularization is a typical occurrence in various viral diseases, the precise mechanism of viral carcinogenesis in these environments may be crucial for the treatment of HIV-associated lymphoma. Therefore, diagnosis and treatment are very important. (228)

3. Antiviral Strategies

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Viral propagation involves exploiting and subverting the cellular machinery of the host through various tactics. The administration of antivirals is vital for reducing the viral load and, thus, propagating the host toward recovery. Antivirals can be derived from natural or chemical sources with varying specificity toward viral strains. In patients with oncological malignancies with prominent or latent hepatitis B or C infection, a nucleoside analogue antiviral therapy successfully prevents virus reactivation. Hepatitis B Ag-positive patients have also reported regression of lymphoma following successful anti-HBV treatment with lamivudine and entecavir. (239) Next, the potential of human papillomavirus to interfere with the proper functioning of the interferon response based on several molecular pathways coordinated by human papillomavirus proteins aimed to prevent infection clearance results in the creation of an immunotolerant environment that promotes the establishment of persistence and cancer. For instance, chemically derived Imiquimod is an immunomodulatory dosage that affects both the innate and adaptive immune responses and the activation of natural killer cells, the production and release of interferon (IFN)-alpha, tumor necrosis factor-alpha, and interleukin-12, in addition to the suppression of viral replication. (240) Cidofovir is another nucleotide analogue that works by inhibiting viral DNA polymerase, and the medication cidofovir also helps to reduce the HPV-positive tumor cells’ propensity for metastasis. (241) Other chemically derived antivirals, such as Ganciclovir, Acyclovir, and Famciclovir, target the viral DNA of the Epstein–Bar virus during the infection stage, thus preventing its progression along with the inhibition of host cell DNA polymerase (Figure 4). In the case of Merkel Cell Polyomavirus infection, a monoclonal antiviral, namely Nivolumab, targets Programmed Cell Death Protein 1 with an eventual inhibitory effect on the hyperactive T cells. Likewise, Ipilimumab targets the CTLA-4 protein causing detrimental defects in the cell repair machinery.
Similarly, natural compounds, such as those found in herbal pharmaceuticals, are also used to search for new antiviral agents. The expression of E6 and E7 viral oncoproteins of human papillomaviruses has the primary role in cervical carcinoma. (242) The primary component of C. longa, curcumin, has an inhibitory effect on the expression of these E6 and E7 genes of two different kinds of HPVs, which are highly oncogenic. Andrographolide, neoandrographolide, dehydro-andrographolide, and several natural and synthetic derivatives possess notable antiviral activity against HIV, influenza A, HBV and HCV without any significant cytotoxic effect at virus-inhibiting concentrations. In addition, naturally derived antivirals from Detarium microcarpum, Bupleurum kaoi, and others help to inhibit viral entry of HCV. Similarly, an antiviral obtained from Eclipta alba, Taraxacum officinale, is known to inhibit HCV’s NS5B replicate activity. Table 2 provides a comprehensive list of antivirals from both chemical and natural sources.
Table 2. A List of Antivirals Obtained Either Chemically or Naturally That Have Varied Activity against Several Oncogenic Viruses
A. Chemical Antivirals
VirusesAntiviralsFunctionsTargetReferences
Epstein–Barr virusGanciclovirPrevent the progression of viral DNA, inhibits host cell DNA polymeraseViral DNA (3)
Acyclovir
Famciclovir
Rituximab (Monoclonal antibody)Targets all B cells expressing CD20 (not specifically target cells containing EBV)B cells
Rapamycin (Immunosuppressive agent)Decrease tumor growth and metastasis in a mouse model of EBV-associated oncogenesisP13K Pathway
Valganciclovir + AlemtuzumabSuppresses replication of EBVReactivation of EBV by targeting CD52 on B- and T-lymphocyte) (248−250)
MaribavirInhibits the EBV protein kinasesViral DNA (251)
CidofovirInhibitors of murine herpesvirus replication and inhibits ribonucleotide reductase (RR)Phosphodiesterase and EBV-transformed epithelial cells/Xenografts (249,251)
RutamarinInhibiting replication of viral DNATopoisomerase II (251)
Hepatitis B and C virusLamivudineHBV DNA chain terminationReverse transcriptase (252)
AdefovirInhibits HBV DNA synthesisReverse transcriptase (252,253)
EntecavirInhibits all steps in the HBV viral replicationHBV polymerase (254,255)
TelbivudineInhibits HBV DNA chain termination and viral replicationSecond strand of DNA and HBV DNA polymerase (reverse transcriptase) (256−258)
TenofovirReverse transcriptase (259)
BoceprevirInhibits viral HCV replication as well as disrupts the processing of viral proteinsHCV nonstructural 3/4A protease inhibitors (252)
Telaprevir 
SofosbuvirExecutes chain termination and prevents viral replication of HCVInhibits HCV NS5B (nonstructural protein 5B) RNA-dependent RNA polymerase (260)
SimeprevirBlocks the function of adapters proteinPolyprotein of HCV (261)
FaldaprevirCleaves the HCV-encoded polyproteinNS3/4A protease (262)
RibavirinDepletion of intracellular GTP and increased hepatitis C virus mutagenesisITP pyrophosphatase (ITPase) (263)
AsunaprevirInhibits viral replicationHCV NS3 protease (264)
DanoprevirPrevents the cleavage and processing of HCV viral proteinsHCV NS3/4A protease (265)
VaniprevirInhibits the enzymatic activityHCV NS3/4A protease (266)
DaclatasvirBlocks both virion assembly/secretion in vivo and intracellular viral RNA synthesisHCV NS5A proteins (267)
LedipasvirPrevents hyperphosphorylation of proteins for viral production (268)
OmbitasvirBlocking signaling interactions and modification of the HCV replication complex (269,270)
Human PapillomavirusCidofovirConverted to its active form as triphosphorylated cidofovir and is likely to induce chain terminationHPV DNA (271,272)
GS-9191Inhibits DNA synthesisDNA polymerase α and ß (273)
ODE-Bn-PMEG/ABI-1968Inhibits HPV origin-dependent plasmid amplificationHPV DNA (274)
AcyclovirInhibits the integration of viral DNA and the replication of cellular DNAHPV DNA (275)
ImiquimodStimulates the innate and acquired immune responses followed by apoptosis of infected tissuesToll-like receptors (276)
CimetidineImproves cellular immunity and wart remissionStimulates Th1 cells to catalyze interleukins (IL)-2, IL-12, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ (276)
BleomycinEliminates pyrimidine and purine bases and affects cellular DNA synthesisCellular DNA (277)
Merkel Cell PolyomavirusPembrolizumabCounteracts its interaction with its known ligandsProgrammed cell death protein 1 
Avelumab1. Blocks the interaction between PD-L1 and its receptors PD-1 and B7.1Programmed cell death 1, Ligand 1 (278,279)
2. Stimulates ADCC in addition to immune checkpoint inhibition
NivolumabPrevents PD-L1 and PD-L2 from inhibiting the action of T cellsProgrammed cell death protein 1 (280)
IpilimumabDefects in the DNA repair machineryCTLA-4 protein (281)
Kaposi Sarcoma HerpesvirusCidofovirInhibitors of murine herpesvirus replication and inhibits ribonucleotide reductase (RR)Phosphodiesterase and EBV-transformed epithelial cells/Xenografts (249)
Ganciclovir1. Prevents the progression of viral DNA, inhibits host cell DNA polymeraseViral DNA (3,282)
2. Reduces plasma viral load of KSHV and can prevent KS in KSHV-seropositive transplant recipients
BortezomibStabilizes the cellular proteins involved in suppressing cellular proliferation and promotes apoptosis, including p21, p27, p53, and I kappa-BHuman 26 S proteasome (283)
Tocilizumab (Antibody)Blocks membrane-bound and soluble gp80 signal transductiongp80 (284)
Siltuximab (Monoclonal antibody)Inhibits binding to soluble and membrane-bound IL-6 receptorsInterleukin 6 (285)
PomalidomideInduces and elevates the B7–2 and ICAM-1 expression in PEL cellsActivation of T cells and NK cell-mediated killing of PEL cells (286)
Bevacizumab (Monoclonal antibody)Exerts its effects by binding and inactivating serum VEGF and is unable to interact with its cell surface receptors, thereby proangiogenic signaling is terminatedVEGF-A, subcomponents subunits (A, B, C), and Affinity Immunoglobulin Fc gamma receptors (286,287)
DoxorubicinComplexes are formed with DNA by intercalation between base pairs, and it inhibits topoisomerase II action by stabilizing the complex of DNA–topoisomerase IIDNA topoisomerase 2-alpha and DNA (288)
Human Immunodeficiency Virus (HIV)Saquinavir + RitonavirHydroxyethylene scaffold mimics the HIV protease for cleaving, thereby carrying out the proteolysis of Gag polyprotein and producing immature and noninfectious particlesHIV protease (289−292)
Lopinavir
Indinavir
Nelfinavir
Amprenavir
Atazanavir
Tipranavir
Darunavir + RitonavirPrevents viral replicationHIV protease (293,294)
LamivudinePrevents the formation of phosphodiester bonds between the Nucleotide Reverse Transcriptase Inhibitors and nucleoside triphosphateReverse transcriptase (295−297)
Zidovudine
Abacavir
Didanosine
Emtricitabine
Stavudine
Zalcitabine
Tenofovir disoprovil fumarate
EntravirineNon-Nucleoside Reverse Transcriptase Inhibitor changes the spatial conformation of the substrate binding site and reduces the polymerase activityReverse transcriptase (298)
Delavirdine
Efavirenz
Nevirapine
Rilpivirine (Phase 3)
Raltegravir1. Binds between the integrase and viral DNA to a specific complexIntegrase (Strand transfer reaction) (299−301)
MK-05182. Interaction takes place between the inhibitor and Mg metal ion in the active site of integrase as well as the DNA
Elvitegravir
Human T-lymphotropic Virus (HTLV)AlemtuzumabBlocks the TAC antigenATLL cells and HTLV1-infected cells (302)
Arsenic trioxide + Interferon-αInduces cell cycle inhibition and apoptosisHTLV1-infected cells and malignant ATLL cells (303,304)
LamivudineCan inhibit viral replication in HTLV1-infected cells in single-use or combination therapyNucleoside analogs (305,306)
Abacavir
Zidovudine
Didanosine
Emtricitabine
Stavudine
Zalcitabine
Tenofovir disoprovil fumarate
RaltegravirPotent to inhibit strand transfer reaction and number of integration of events directlyHTLV1 Integrase (307)
Romidepsin1. Can suppress the expression of NF-κB and AP-1ATLL cells and HTLV1-infected cells (308,309)
2. Induces apoptosis of HTLV-1 infected cells and ATLL cells
NiclosamideInduces degradation in protein and inhibits viral gene transcription of HTLV1Tax protein (310)
Chondroitin Sulfate Type EInteracts with the recombinant envelope protein of the virus at the C-terminus and blocks the binding of the virus to the human T cellHuman T cell (311)
DarunavirPrevents viral replicationHTLV1 Protease (312)
Arsenic trioxide + Interferon-αInduces cell cycle inhibition and apoptosisHTLV1-infected cells and malignant ATLL cells (303,304)
B. Natural Antivirals
AntiviralsFunctionVirus/TargetReferences
Terminalia bellericaInhibits viral entry, replication, and maturation of HBV particlesHepatitis B virus (313−315)
Phyllanthus Amarus
Hybanthusenneaspermus
Enicostemmaaxillare
Bombyx mori L
Boehmeria nivea
TrichiliadregeanaInhibits viral entryHepatitis C virus
Detarium microcarpum
Phragmanthera capitata
Bupleurum kaoi
Anthocyanidin
AlloeocomatellapolycladiaSuppression of the helicase activity of HCV NS3
Fusarium equisetiInhibition of HCV NS3/4A protease
Eclipta albaInhibition of HCV NS5B replicase activity
Taraxacum officinale
Swietenia macrophyllaReduction of HCV protein and HCV–RNA levels
Entada africanaBroad antiviral activity
Grape seedSuppression of HCV-induced Cox-2
FlavanoneRelease/Assembly
Curcuma longaLInhibits immediate–early gene expressionHerpes simplex virus 1
Houttuynia cordataBlocks viral binding and suppresses NF-κB activationHerpes simplex virus 1
Herpes simplex virus 2
Pistacia vera LInhibits expression of HSV-1 viral proteins and viral DNA synthesisHerpes simplex virus 1
Prunus dulcisBlocks viral binding
Aloe VeraReduction of cytopathic effect (CPE)
CephalotaxaceaeTargets the cellular factor eIF4E
Curcuma longa LDownregulating expression of oncogenes E6 and E7HPV-16
HPV-18
Ficus caricaHPV-16
C. longa, A. indica, E. officinalis, A. veraPrevents the entry of HPV 16 in Hela cells
Green teaPromoting apoptosis and inhibiting cellular transcriptional factors
PinelliapedatisectaHPV-16
HPV-18
CudraniatricuspidataHPV-16
Curcuma longa LHPV-18
HPV-16
Bryophyllum pinnataHPV-18
Phyllanthus emblicaHPV-16
HPV-18
Kaempferia parvifloraHPV-16
PodophyllumMitotic arrest in cell cycleGenital warts (316)
Nostoc ellipsosporumBreaching inhibitorsHIV (313−315)
Griffithsia sp.
Stellettaclavosa
Siliquariaspongia mirabilis
SyzygiumclaviflorumMaturation inhibitors
Synthetic derivative of betulinic acid
Rheum palmatumIntegrase inhibitors and reverse transcriptase
Morus nigra
Justica gendarussa
Calophyllumlanigerum
Euphorbia kansuiLatency-reversing agents
Theobroma cacao
Andrographis paniculataInhibits transcription of IE genes in EVB and the production of virionsEpstein–Barr Virus (249)
Polygonum cuspidatumInhibits the lytic cycle of EBV
Saururus chinensisInhibits replication of EBV lytic cycle
Rhus chinensisReduces the number of EBV particles
Thelypteris torresianaInhibiting the EBV virus lytic cycle
Psoralea corylifoliaInhibits early steps of the replicative lytic cycle in EBV
Angelica archangelica
BorrelidinInhibits tRNA synthesisMerkel Cell Carcinoma (317)
MechlorethamineCauses DNA damage
PlumbaginROS/redox-active, proteasome
Mitomycin CCauses DNA damage
CladribineInhibits DNA synthesis
Clofarabine
Pyrrolidine dithiocarbamateROS, proteasome, NFκB
EtoposideTopoisomerase II/causes DNA damage
GloxazoneInhibits DNA synthesis
PanobinostatHistone deacetylase inhibitors/ROS active
DisulfiramROS, proteasome, NF-κB
ThapsigarginStress on the endoplasmic reticulum
Englerin AProtein Kinase C
FuroxanobenzofuroxanInhibits monoamine oxidase
5-Nitroso-8-quinolinolHistone deacetylase inhibitors/ROS active
Phytolacca americanaDepurinates nucleotides/feedback inhibition of HTLV-I gene expressionHuman T-lymphotropic virus 1 (318)
Scutellaria baicalensis georgiInhibits reverse transcriptase activity in HTLV-I-infected cells (319)
Curcumin metabolites (Curcumin-sulfate, curcumin-glucuronide, and tetrahydro-curcumin)Potent HTLV1 protease inhibitors (320)
OleandrinInhibits virological synapse formation (321)
These chemicals and naturally derived antiviral drugs have been reported and shown their potential for viral oncogenesis therapies (Figure 4). Several studies have reported on the effectiveness of antiviral drugs in preventing oncogenesis. In 2008, a study by Yoshizaki et al. reported the antitumor potential of cidofovir against nasopharyngeal carcinoma (NPC). Two patients whose earlier multi-round therapy was treated with cidofovir once every three weeks (75 mg/mL solution diluted to 15 mg/mL just before injection) showed a reduction in the tumor cell population. (243) In 2017, Shaimerdenova et al. studied the effect of the antiviral agent acyclovir on the MCF7 breast cancer cell line. The study reported that acyclovir treatment decreases cancer cell proliferation, colony formation ability, and cell invasion capacity by up-regulating Caspase-3 and down-regulating aldehyde dehydrogenase (ALDH) activity. (244) Mattson et al. reported in 2009 that zidovudine treatment combined with the chemotherapeutic agent cisplatin had increased the apoptosis level of head and neck cancer cells. The combination synergistically triggers abnormal regulation of the mitochondria by increased oxidative stress response and significant cytotoxic effect on the cancer cell through inhibiting thiol metabolism. (245) Recently, Huang et al. in 2021 reported the differential effect of oseltamivir in inducing liver cancer cell death both in vitro and in vivo. Treatment with oseltamivir decreased migration and invasion of liver cancer cells and increased autophagy in Huh-7 cells. (246) Urtishak et al. also reported that the antiviral drug ribavirin decreased the elevated level of EIF4E protein in most cases of infant acute lymphoblastic leukemia (ALL). (247) In this study it has been reported that treating ribavirin by actively dividing infant ALL cells into bone marrow stromal cells (BMSCs) at clinically achievable concentrations decreases oncogenic EIF4E-regulated cell growth and survival proteins.

Figure 4

Figure 4. Different antiviral agents to curb the action of oncogenic viruses on the molecular front (Created by Biorender).

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4. Recent Progress on Drug Developments for Oncogenic Virus

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The existing challenges toward developing new drugs to prevent virus-associated cancer have heated up in recent years. Much more research is being conducted to have some positive outcomes that could be translated. For instance, the NCT03783078 trial primarily investigated pembrolizumab as a first-line therapy for advanced Merkel cell carcinoma. Pembrolizumab falls under the category of a monoclonal antibody that obstructed the interaction of programmed death receptor-1 (PD-1) with programmed death ligand-1(PD-L1) and PD-L2, thereby inhibiting antitumor immune response. (322) Another trial NCT01472263 has primarily focused on the safety interventional studies of the drug Pentoxifylline in HTLV1 patients. Pentoxifylline falls under the category of methylxanthine molecules that inhibit the action of phosphodiesterase type IV, which in turn delays the degradation process of cAMP and prostanoids. The activity of NF-κB and NF-AT transcription factors gets disrupted with the high influx of intracellular cAMP, eventually inhibiting TNF-α production, thus deregulating the action of HTLV1. (323)
The NCT02346227 randomized placebo-controlled trial essentially puts weight on the safety studies of AV2 for HPV-associated lesions of the uterine cervix. A complex combination of naturally available essential oils, namely, carvone, eugenol, geraniol, and nerolidol, constitutes an antiviral formulation named Antiviral 2 developed by Cesa Alliance, Luxembourg. The essential oils have already received FDA approval, and their antiviral effect is well documented. As per reports, antiviral 2 formulations have been shown to inhibit viral replication by degenerating HPV-induced cervical lesions. (324,325) This NCT00002445 trial primarily focuses on the safety and effectiveness of intranasal-based IM862 drug formulation in treating Kaposi’s Sarcoma/HHV-8 in AIDS Patients. Chemically, IM862 is derived as a dipeptide from L-glutamyl-L-tryptophan. IM862 helps to inhibit tumor angiogenesis, which gives rise to new blood vessels that provide a redundant nutrition supply to the tumor cells. The action of IM862 is executed through the upregulation of natural killer cell activity and the inhibition of vascular endothelial growth factor. (326) The NCT02640482 primarily investigates ABT-493 efficacy and safety of ABT-493/ABT-530 in adults with chronic HCV Type 2 infection. ABT-493 is an antagonist of the HCV nonstructural (NS) protein 3/4A protease, while ABT-530 is an antagonist of the HCV NS5A protease. These substances exhibit strong in vitro-based antiviral efficacy against all key HCV genotypes. (327) One more instance of progress has been reported where NCT00805675 primarily focuses on the effects of telbivudine and tenofovir disoproxil fumarate treatment for HBV DNA. As it is a transparent, passively regulated viral kinetics study, the participant and the physician would know the investigative medicine administered to each patient. Telbivudine is classified as an L-nucleoside that exhibits structural similarity with lamivudine. The action of telbivudine is highly specific in nature as it targets the HBV DNA synthesis process without disrupting human DNA or other viral strains. (328,329) Some other drug clinical trials for targeting the oncogenic viruses are listed in Table 3.
Table 3. Completed Clinical Trials Conducted for Drugs Relevant to the Following Oncogenic Virusesa
S. No.TitleInterventionOutcome measuresSponsors/ CollaboratorsPhaseEnrollmentNCT Number
(i) MCPyV
1.Pembrolizumab (MK-3475) as First-line Therapy for Advanced Merkel Cell Carcinoma (MK-3475-913)Drug: Pembrolizumab (MK-3475)Objective Response Rate (ORR), Duration of Response (DOR), Progression-free Survival (PFS), Overall Survival (OS), Number of Participants with One or More Adverse Events (AEs), Number of Participants Who Discontinued from Study Treatment Due to an AEMerck Sharp & Dohme LLCPhase 355NCT03783078 (https://ClinicalTrials.gov/show/NCT03783078, Accessed on 22 March 2023)
2.Testing Pembrolizumab Versus Observation in Patients with Merkel Cell Carcinoma After Surgery, STAMP StudyOther: Best Practice, Procedure: Biospecimen Collection, Procedure: Computed Tomography, Biological: Pembrolizumab, Procedure: Positron Emission Tomography, Radiation: Radiation TherapyRecurrence-free survival (RFS), OS, Impact of radiation therapy on RFS, Impact of radiation therapy on OS, Impact of radiation therapy on distant metastasis-free survival (DMFS), Incidence of adverse eventsNational Cancer Institute (NCI)Phase 3280NCT03712605 (https://ClinicalTrials.gov/show/NCT03712605, Accessed on 22 March 2023)
3.Adjuvant Avelumab in Merkel Cell CancerDrug: Avelumab, Other: Peripheral Blood Collection, Other: PlaceboRelapse-free survival, Disease-specific survival, Distant-metastases free survival, Incidence of adverse events, Overall survivalUniversity of Washington, EMD SeronoPhase 3100NCT03271372 (https://ClinicalTrials.gov/show/NCT03271372, Accessed on 22 March 2023)
4.Evaluating Length of Treatment With PD-1/PD-L1 Inhibitor in Advanced Solid TumorsDrug: Continue PD-1/PD-L1 Inhibitors treatment; other: Discontinue PD-1/PD-L1–1 inhibitorTime to next treatment, Progression-free Survival (PFS) (at between 2 and 3.9 months), Progression-free Survival (PFS) (at between 4 and 7.9 months), Progression-free Survival (PFS), Incidence of irAEs (Immune-Related Adverse Events), Overall Survival (OS), Best Objective Response (BOR)Jason J. Luke, MD, University of PittsburghPhase 3578NCT04157985 (https://ClinicalTrials.gov/show/NCT04157985, Accessed on 22 March 2023)
5.Study Comparing the Standard Administration of IO Versus the Same IO Administered Each 3 Months in Patients with Metastatic Cancer in Response After 6 Months of Standard IODrug: Reduced dose intensity of IOProgression-free survival (PFS), Cost-effectiveness analysis of the proposed therapeutic strategy, Immune progression-free survival (iPFS), Objective response rate (ORR), Overall survival (OS), Duration of response (DoR), Quality of life questionnaire - Core 30 (QLQ-C30), The Developed 5-level version of EQ-5D (EQ-5D-5L) questionnaire, Hospital anxiety and depression scale (HADS), Fear of relapse questionnaire, Safety profileUNICANCERPhase 3646NCT05078047 (https://ClinicalTrials.gov/show/NCT05078047, Accessed on 22 March 2023)
(ii) HTLV1
1.Use of Pentoxifylline in Human T-lymphotropic Virus Type-1 (HTLV-1) DiseasesDrug: Pentoxifylline, Drug: PlaceboFunctional neurological capacity, Reduced in cytokines and chemokinesHospital Universitario Professor Edgard SantosPhase 348NCT01472263 (https://ClinicalTrials.gov/show/NCT01472263, Accessed on 22 March 2023)
2.Zidovudine Plus Lamivudine in HTLV-I-associated Myelopathy: A Randomized TrialDrug: Zidovudine/lamivudine, Drug: PlacebosTimed walk, Osame’s Motor Disability Score, Pain score, Urinary frequency, HTLV-1 proviral load, CD25%, HLA-DR%Imperial College LondonPhases 2 and 316NCT00272480 (https://ClinicalTrials.gov/show/NCT00272480, Accessed on 22 March 2023)
3.Ciclosporin in HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP)Drug: CiclosporinNumber of Patients with Lack of Objective Clinical Improvement, Change in Timed Walk Sl. No. Between Baseline and 12 WeeksImperial College London, Medical Research Council, University Hospital Birmingham, Imperial College Healthcare NHS TrustPhases 2 and 37NCT00773292 (https://ClinicalTrials.gov/show/NCT00773292, Accessed on 22 March 2023)
4.Use of Valproic Acid to Treat Tropical Spastic Paraparesis/HTLV-1-Associated Myelopathy (TSP/HAM)Drug: Valproic acid, Drug: Corticosteroids, Drug: valproic acid plus corticosteroidsNeurological scales, Quality of lifeUniversity of Sao PauloPhase 360NCT00681980 (https://ClinicalTrials.gov/show/NCT00681980, Accessed on 22 March 2023)
5.Pilot Study of Combination Therapy With CHOP-Zenapax (CHOP-daclizumab)Drug: CHOP-daclizumab King’s College Hospital NHS TrustPhase 4 NCT01418430 (https://ClinicalTrials.gov/show/NCT01418430, Accessed on 22 March 2023)
(iii) HPV
1.Impact of AV2 Antiviral Drug on the Treatment of HPV-associated Lesions of the Uterine CervixDrug: AV2, Drug: PlaceboChange of lesions, absence of HPV DNA, the correlation between change of lesions and change in HPV DNA, Change in HPV viral particle loadJean-Pierre Van Geertruyden, University of Kinshasa, University Hospital, Antwerp, Universiteit AntwerpenPhase 3327NCT02346227 (https://ClinicalTrials.gov/show/NCT02346227, Accessed on 22 March 2023)
2.Recombinant Human Interferon a-2b Gel for HPV Gynaecological InfectionsDrug: YallaferonThe difference in hr-HPV DNA negative conversion rate, Secondary efficacy end points were the differences of single-type HPV infection, dual infection, and multiple infections in the sixth month between the two groupsLee’s Pharmaceutical LimitedPhases 2 and 3325NCT01824992 (https://ClinicalTrials.gov/show/NCT01824992, Accessed on 22 March 2023)
3.Study of the Efficacy and Safety of the Drug Ingaron (Interferon-gamma) in the Treatment of Anogenital WartsDrug: Interferon-gamma human recombinant (IFN-G)Recurrence of anogenital wartsSPP Pharmaclon Ltd.Phase 330NCT05156541 (https://ClinicalTrials.gov/show/NCT05156541, Accessed on 22 March 2023)
4.Delivery, Uptake and Acceptability of HPV Vaccination in Tanzanian GirlsBiological: Gardasil HPV vaccineVaccine coverage by delivery strategy, Vaccine coverage (dose 2) by delivery strategy, Vaccine coverage (dose 1) by delivery strategy, Factors associated with refusal to vaccinate or to complete vaccination course, Identification of barriers to HPV vaccination, Estimation of the costs of introducing and scaling up HPV vaccines in schoolsLondon School of Hygiene and Tropical Medicine, National Institute for Medical Research, Tanzania, Ocean Road Cancer Institute, Tanzania, Institut Catalan d’ Oncologia, Spain, Medical Research Council Social & Public Health Sciences Unit, UK, International Union Against Cancer, SwitzerlandPhase 45532NCT01173900 (https://ClinicalTrials.gov/show/NCT01173900, Accessed on 22 March 2023)
5.Immunogenicity and Safety of Dengue Tetravalent Vaccine (TDV) and Recombinant 9-valent Human Papillomavirus Vaccine (9vHPV) in Participants Aged 9 to < 15 YearsBiological: 9vHPV vaccine, Biological: Dengue Tetravalent Vaccine (TDV)Geometric Mean Titers (GMTs) for Human Papillomavirus (HPV) Types 6, 11, 16, 18, 31, 33, 45, 52, and 58, Percentage of Participants with Seropositivity for HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 as Measured by Immunoglobulin G Binding Assay (IgGBA) or Equivalent Assay, GMTs of Neutralizing Antibodies for Each of the 4 Dengue Serotypes, Percentage of Participants with Seropositivity for Each of the 4 Dengue Serotypes, Percentage of Participants with Seropositivity for Multiple (2, 3, or 4) Dengue Serotypes, Percentage of Participants with Solicited Local Reactions for 7 Days Following Vaccination by Severity, Percentage of Participants with Solicited Systemic Adverse Events (AEs) for 14 days Following Vaccination by Severity, Percentage of Participants with any Unsolicited AEs for 28 days Following Vaccination, Percentage of Participants with Serious Adverse Events (SAEs)TakedaPhase 3618NCT04313244 (https://ClinicalTrials.gov/show/NCT04313244, Accessed on 22 March 2023)
6.Safety and Immunogenicity of Human Papillomavirus (HPV) Vaccine in Solid Organ Transplant RecipientsBiological: Human papillomavirus quadrivalent vaccineThe primary outcome will be a 2-fold rise in the type-specific HPV titer for at least one of the four serotypes contained in the vaccine at month 7, Vaccine adverse events, including episodes of rejection up to 1 year after study enrolment, Immunogenicity at 36 months postvaccination.University of AlbertaPhase 350NCT00677677 (https://ClinicalTrials.gov/show/NCT00677677, Accessed on 22 March 2023)
7.Immunogenicity and Safety of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Patients With SLE: a Controlled StudyDrug: human papillomavirus vaccination (Gardasil)Antibody titers against 4 strains of human papillomavirusTuen Mun HospitalPhase 4100NCT00911521 (https://ClinicalTrials.gov/show/NCT00911521, Accessed on 22 March 2023)
(iv) KSHV
1.Safety and Effectiveness of an Experimental Drug, IM862, in Treating Kaposi’s Sarcoma in AIDS PatientsDrug: IM862 Cytran, NIH AIDS Clinical Trials Information ServicePhase 3200NCT00002445 (https://ClinicalTrials.gov/show/NCT00002445, Accessed on 22 March 2023)
2.Antiretroviral Therapy (ART) Alone or With Delayed Chemo Versus ART With Immediate Chemo for Limited AIDS-related Kaposi’s SarcomaDrug: efavirenz/emtricitabine/tenofovir disoproxil fumarate, Drug: etoposideKaposi Sarcoma (KS) Status at Week 48 Compared to Study Entry, KS Progressive Disease at Week 48 Compared to Study EntryAIDS Clinical Trials Group, National Institute of Allergy, and Infectious Diseases (NIAID)Phase 3192NCT01352117 (https://ClinicalTrials.gov/show/NCT01352117, Accessed on 22 March 2023)
3.HIV/AIDS Kaposis Sarcoma: Comparison of Response to HAART vs HAART Plus CXTDrug: Generic HAART Triomune: d4T, 3TC, NVP, Drug: Generic HAART Triomune: d4T, 3TC, NVP, and chemotherapy ABVClinical response of KS, Skin: tumor measurements of 5 indicator skin lesions. Assessment of KS as per AMC RKS 02 (www.amc.uab.edu), photography of indicator lesions with metric tape in the frame, Visceral: chest radiograph and endoscopy, where necessary, bronchoscopy, Safety and toxicity by DAIDS Toxicity criteria, Immunological and virological response to HAART as measured by CD4 and HIV-viral load, QOL by EORTC QLQ C30, AdherenceUniversity of KwaZulu, AIDS Care Research in Africa, National Research Foundation, Singapore, AIDS Malignancy Consortium, Cipla Medpro, Dermatological Society of South AfricaPhase 4112NCT00380770 (https://ClinicalTrials.gov/show/NCT00380770, Accessed on 22 March 2023)
4.Use of Stealth Liposomal Doxorubicin HCl (DOX-SL) in the Treatment of Moderate to Severe AIDS-Related Kaposi’s Sarcoma.Drug: Doxorubicin hydrochloride (liposomal) Sequus Pharmaceuticals, NIH AIDS Clinical Trials Information ServicePhase 3 NCT00002147 (https://ClinicalTrials.gov/show/NCT00002147, Accessed on 22 March 2023)
5.A Pilot Study of the Effects of Highly Active Antiretroviral Therapy on Kaposi’s Sarcoma in ZimbabweDrug: abacavir/3TC/zidovudine, Drug: abacavir /3TC plus ritonavir boosted lopinavirCompare effects of twice-daily all-(NRTI) antiretroviral regimen to a once-daily regimen of 2 NRTIs plus a protease inhibitor AIDS-KS subjects with good virologic suppression on all-NRTI regimen.Parirenyatwa Hospital, University of Colorado, Denver, GlaxoSmithKline, AbbottPhases 2 and 349NCT00834457 (https://ClinicalTrials.gov/show/NCT00834457, Accessed on 22 March 2023)
6.A Study of DOX-SL in the Treatment of AIDS-Related Kaposi’s SarcomaDrug: Doxorubicin hydrochloride (liposomal) Sequus Pharmaceuticals, NIH AIDS Clinical Trials Information ServicePhase 3 NCT00002319 (https://ClinicalTrials.gov/show/NCT00002319, Accessed on 22 March 2023)
7.Paclitaxel Compared with Doxorubicin in Treating Patients with Advanced AIDS-Related Kaposi’s SarcomaDrug: paclitaxel, Drug: pegylated liposomal doxorubicin hydrochloride, Other: laboratory biomarker analysis, Procedure: quality-of-life assessmentProgression-free survival, Patients’ health-related quality of life (QOL) in terms of change in pain score, e Antibody titers edema-related mobility, gastrointestinal (GI) symptoms and respiratory symptoms based on the total score from the Functional Assessment of HIV Infection (FAHI) v3National Cancer Institute (NCI)Phase 3240NCT00003350 (https://ClinicalTrials.gov/show/NCT00003350, Accessed on 22 March 2023)
8.Randomized, Comparative Trial of DOX-SL (Stealth Liposomal Doxorubicin Hydrochloride) Versus Bleomycin and Vincristine in the Treatment of AIDS-Related Kaposi’s SarcomaDrug: Doxorubicin hydrochloride (liposomal), Drug: Bleomycin sulfate, Drug: Vincristine sulfate Sequus Pharmaceuticals, NIH AIDS Clinical Trials Information ServicePhase 3220NCT00002105 (https://ClinicalTrials.gov/show/NCT00002105, Accessed on 22 March 2023)
9.Doxorubicin in Treating Patients With AIDS-Related Kaposi’s SarcomaDrug: daunorubicin hydrochloride, Drug: pegylated liposomal doxorubicin hydrochloride Roswell Park Cancer InstitutePhase 3 NCT00002985 (https://ClinicalTrials.gov/show/NCT00000994, Accessed on 22 March 2023)
10.A Randomized Phase III Clinical Trial of Daunoxome Versus Combination Chemotherapy with Adriamycin/Bleomycin/Vincristine (ABV) in the Treatment of HIV-Associated Kaposi’s Sarcoma.Drug: Daunorubicin (liposomal), Drug: Bleomycin sulfate, Drug: Vincristine sulfate, Drug: Doxorubicin hydrochloride Nexstar Pharmaceuticals, NIH AIDS Clinical Trials Information ServicePhase 3 NCT00002093 (https://ClinicalTrials.gov/show/NCT00000994, Accessed on 22 March 2023)
11.A Study of AZT in HIV-Infected Patients With AIDS-Related Kaposi’s SarcomaDrug: Zidovudine National Institute of Allergy and Infectious Diseases (NIAID)Phase 3240NCT00000994 (https://ClinicalTrials.gov/show/NCT00000994, Accessed on 22 March 2023)
12.Anti-Retrovirals for Kaposi’s SarcomaDrug: Lopinavir/ritonavir plus Emtricitabine/Tenofovir versus Efavirenz plus Emtricitabine/TenofovirBlinded assessment of the change in the burden of KS lesions, CD4+ T cell count and HIV plasma HIV RNA levels, KSHV DNA levels in saliva and blood, Humoral and cellular KSHV immune response markers, Quality-of-life assessment, Incidence of Kaposi’s sarcoma-associated Immune Reconstitution Inflammatory Syndrome (KS-IRIS)University of California, San Francisco, National Institutes of Health (NIH), Gilead Sciences, Abbott, Merck Sharp & Dohme LLCPhase 4224NCT00444379 (https://ClinicalTrials.gov/show/NCT00444379, Accessed on 22 March 2023)
(v) HCV
1.A Study to Evaluate the Efficacy and Safety of ABT-493/ABT-530 in Adults with Chronic Hepatitis C Virus (HCV) Genotype 2 InfectionDrug: ABT-493/ABT-530, Drug: Placebo for ABT-493/ABT-530Percentage of Participants with Sustained Virologic Response 12 Weeks Post-treatment (SVR12) in Arm A DB Active Drug Excluding Prior SOF + Ribavirin (RBV)AbbViePhase 3304NCT02640482 (https://ClinicalTrials.gov/show/NCT02640482, Accessed on 22 March 2023)
2.Treatment of Acute Hepatitis C Virus Infection with Pegylated Interferon in Injection Drug UsersDrug: Pegylated InterferonThe sustained viral response rate in the treatment group versus control (measured at Week 24), Adherence rate in the treatment group (measured at Week 24)National Institute on Drug Abuse (NIDA), University of WashingtonPhase 421NCT00194480 (https://ClinicalTrials.gov/show/NCT00194480, Accessed on 22 March 2023)
3.Drug Use & Infections in Vietnam - Hepatitis C (DRIVE-C)Drug: Sofosbuvir 400 mg and Daclatasvir 60 mg, Drug: Sofosbuvir 400 mg and Daclatasvir 90 mg, Drug: Ribavirin, Drug: Sofosbuvir and Daclatasvir for 24 weeksThe proportion of all patients with the success of the model of care, the Proportion of patients with detectable HCV RNAANRS, Emerging Infectious DiseasesPhase 4979NCT03537196 (https://ClinicalTrials.gov/show/NCT03537196, Accessed on 22 March 2023)
4.A Study to Evaluate the Efficacy and Safety of Three Experimental Drugs in Adults with Hepatitis C Virus Infection, Who Are Either Treatment-naive or Treatment-experienced in BrazilDrug: ombitasvir/paritaprevir/ritonavir and dasabuvir, Drug: ribavirinPercentage of Participants with Sustained Virologic Response 12 Weeks Post-treatment (SVR12), Change from Baseline to 12 Weeks After the Last Dose of Study Drug, (SF-36v2) Mental Component Summary (MCS) Scores: Change from Baseline to 12 Weeks After the Last Dose of Study DrugAbbViePhase 3222NCT02442271 (https://ClinicalTrials.gov/show/NCT02442271, Accessed on 22 March 2023)
5.Pegylated Interferon Plus Ribavirin in the Treatment of Active and Past Intravenous Drug Users Infected with Hepatitis CDrug: pegylated interferon alfa-2a (Roche) and ribavirinSustained viral responseThe University of Calgary, Canadian Institutes of Health Research (CIHR), Roche Pharma AGPhase 466NCT00203606 (https://ClinicalTrials.gov/show/NCT01773070, Accessed on 22 March 2023)
6.A Follow-up Study Designed to Obtain Long-Term Data on Participants Who Either Achieved a Sustained Virologic Response or Did Not Achieve a Sustained Virologic Response in an AbbVie Sponsored Hepatitis C StudyDrug: ABT-450/ritonavir, Drug: ABT-333, Drug: ABT-267Percentage of Participants Who Experienced Relapse-12 overall With and Without New HCV InfectionAbbVie (prior sponsor, Abbott), AbbViePhase 3478NCT01773070 (https://ClinicalTrials.gov/show/NCT01773070, Accessed on 22 March 2023)
7.Pilot Treatment as Prevention for HCV Among Persons Who Actively Inject DrugsOther: modified directly observed therapy (mDOT), Other: unobserved dosing, Other: Motivational Interviewing-based counselingNumber of people who inject drugs (PWIDs) with HCV who were recruited and retained, Medication adherence to study drug, Challenges of medication adherence, SVR (end-of-treatment response), SOF/metabolite levels, HCV relapse and reinfection, Social and injector networks of participantsPhillip Coffin, MD, MIA, National Institute on Drug Abuse (NIDA), San Francisco Department of Public HealthPhase 431NCT02609893 (https://ClinicalTrials.gov/show/NCT02609893, Accessed on 22 March 2023)
8.Hepatitis C Treatment in PWIDs: MAT or Syringe Exchange Assisted-therapy vs Standard of CareDrug: elbasvir-grazoprevir (50 mg/100 mg)SVR 12, SVR 48, Discontinuation Rate or Lost to Follow Up, NS5A Resistance, Medication Adherence, Injection Drug Use Relapse (IDU)Oregon Health and Science UniversityPhase 4100NCT03093415 (https://ClinicalTrials.gov/show/NCT03093415, Accessed on 22 March 2023)
9.A Trial to Reduce Hepatitis C Among Injection Drug Users - 1Behavioral: Behavior TherapyHepatitis C seroconversion, Substance useButler Hospital, National Institute on Drug Abuse (NIDA)Phase 3277NCT00218192 (https://ClinicalTrials.gov/show/NCT00218192, Accessed on 22 March 2023)
10.A Study to Evaluate the Efficacy and Safety of Three Experimental Drugs Compared with Telaprevir (a Licensed Product) in People with Hepatitis C Virus Infection Who Have Not Had Treatment BeforeDrug: ABT-450/r/ABT-267, ABT-333, Drug: Ribavirin, Drug: Telaprevir, Drug: Pegylated Interferon-alpha 2-a (PegIFN)Percentage of Participants with Sustained Virologic Response 12 Weeks After Treatment (SVR12), Percentage of Participants with Sustained Virologic Response 24 Weeks After Treatment (SVR24)AbbViePhase 3311NCT01854697 (https://ClinicalTrials.gov/show/NCT01854697, Accessed on 22 March 2023)
(vi) HBV
1.Effects of Telbivudine and Tenofovir Disoproxil Fumarate Treatment on the Hepatitis B Virus DNA Kinetics in CHBDrug: Telbivudine, Drug: Tenofovir, Drug: Telbivudine plus tenofovirChange in Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Level from Baseline to Week 12 Phase 383NCT00805675 (https://ClinicalTrials.gov/show/NCT00805675, Accessed on 22 March 2023)
2.Effects of Telbivudine and Tenofovir Disoproxil Fumarate Treatment on the Hepatitis B Virus DNA Kinetics in CHBDrug: Telbivudine, Drug: Tenofovir, Drug: Telbivudine plus tenofovirChange in Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Level from Baseline to Week 12 Phase 3109NCT00395018 (https://ClinicalTrials.gov/show/NCT00395018, Accessed on 22 March 2023)
3.TDF VS LAM + ADV in LAM + ADV Treated LAM-resistant CHB Patients with Undetectable Hepatitis B Virus DNADrug: Lamivudine plus adefovir, Drug: TenofovirPercentage number of patients with virus reactivation, Virologic response, Antiviral resistance, Biochemical response, Serologic response, Safety assessment Phase 4171NCT01732367 (https://ClinicalTrials.gov/show/NCT01732367, Accessed on 22 March 2023)
4.Evaluation of Tenofovir Disoproxil Fumarate in Adolescents with Chronic Hepatitis B InfectionDrug: Tenofovir disoproxil fumarate (TDF), Drug: PlaceboPercentage of Participants with HBV DNA < 400 copies/mL at Week 72 Phase 3106NCT00734162 (https://ClinicalTrials.gov/show/NCT00734162, Accessed on 22 March 2023)
5.A Study of Maraviroc In HIV Co-Infected Subjects With Hepatitis C and Hepatitis BDrug: Maraviroc, Drug: PlaceboPercentage of Participants with grade 3 and grade 4 Alanine Aminotransferase (ALT) Abnormalities at Week 48 Phase 4138NCT01327547 (https://ClinicalTrials.gov/show/NCT01327547, Accessed on 22 March 2023)
6.Viral Kinetics Study of Telbivudine and Entecavir in Adults with Chronic Hepatitis BDrug: Entecavir, Drug: TelbivudineChange in Mean Hepatitis B Virus (HBV) DNA Levels, Change in Mean HBV DNA Level, The Area Under the Curve (AUC) of HBV DNA Change, Change in Alanine Aminotransferase (ALT) Levels, Characterization of Very Early Viral Kinetics: Estimation of Viral Clearance, Characterization of Very Early Viral Kinetics: Estimation of the Rate of Infected Cell Loss, Characterization of Very Early Viral Kinetics: Estimation of the Efficiency Factor of Blocking Virus Production, Number of Patients Who Are Polymerase Chain Reaction (PCR) Negative Phase 344NCT00412529 (https://ClinicalTrials.gov/show/NCT03468907, Accessed on 22 March 2023)
(vii) EBV
1.Belatacept 3 Month Post Transplant Conversion StudyDrug: belatacept, Drug: Tacrolimus, Drug: MPAChange in eGFR (MDRD) at 2 Years Post-transplant Compared to Baseline at Month 3 (Conversion), Acute Rejection, Graft Survival, Patient SurvivalLorenzo Gallon, Bristol-Myers Squibb, Northwestern UniversityPhase 428NCT02213068 (https://ClinicalTrials.gov/show/NCT02213068, Accessed on 22 March 2023)
2.A Trial of Adjuvant Chemotherapy in Nasopharyngeal Carcinoma Patients with Residual Epstein–Barr Virus (EBV) DNA Following RadiotherapyDrug: Adjuvant chemotherapy (gemcitabine and cisplatin)Relapse-free survival, Overall survival, Loco-regional control, Metastasis-free survival, Toxicity of adjuvant chemotherapy, Correlation of plasma EBV DNA and PET/CT scan with clinical course and outcomeChinese University of Hong Kong, Hong Kong Nasopharyngeal Cancer Study Group LimitedPhase 3104NCT00370890 (https://ClinicalTrials.gov/show/NCT00370890, Accessed on 22 March 2023)
3.A Phase III Trial Evaluating Chemotherapy and Immunotherapy for Advanced Nasopharyngeal Carcinoma (NPC) PatientsBiological: autologous EBV-specific Cytotoxic T cells, Drug: a combination of IV gemcitabine and IV carboplatin (AUC2)Prolonging Overall Survival, Disease Progression, Overall Response Rate, Clinical Benefit Rate, and Quality of Life of patientsTessa TherapeuticsPhase 3330NCT02578641 (https://ClinicalTrials.gov/show/NCT02578641, Accessed on 22 March 2023)
4.Efficacy and Safety Study of Lenalidomide Plus R-CHOP Chemotherapy Versus Placebo Plus R-CHOP Chemotherapy in Untreated ABC Type Diffuse Large B-cell LymphomaDrug: lenalidomide, Drug: Placebo, Drug: Rituximab, Drug: Cyclophosphamide, Drug: Doxorubicin, Drug: prednisone, Drug: vincristine CelgenePhase 3570NCT02285062 (https://ClinicalTrials.gov/show/NCT02285062, Accessed on 22 March 2023)
5.Newly Diagnosed Mature B-ALL, Burkitt’s Lymphoma and Other High-grade Lymphoma in AdultsDrug: Adriamycin, Drug: Cyclophosphamide, Drug: Cytarabine, Drug: Dexamethasone/Prednisolone, Drug: VP16, Drug: Ifosfamide, Drug: Methotrexate, Drug: G-CSF, Drug: Rituximab, Drug: Vincristine/Vindesine, Procedure: Irradiation (in specific conditions) Nicola Goekbuget, Goethe UniversityPhase 4650NCT00199082 (https://ClinicalTrials.gov/show/NCT00199082, Accessed on 22 March 2023)
6.Double Cord Versus Haploidentical (BMT CTN 1101)Biological: Haploidentical Bone Marrow Transplant, Biological: Double Umbilical Cord Blood Transplant Medical College of Wisconsin, National Heart, Lung, and Blood Institute (NHLBI), National Cancer Institute (NCI), Blood and Marrow Transplant Clinical Trials Network, National Marrow Donor ProgramPhase 3368NCT01597778 (https://ClinicalTrials.gov/show/NCT01597778, Accessed on 22 March 2023)
7.Interleukin-2 or Observation Following Radiation Therapy, Combination Chemotherapy, and Peripheral Stem Cell Transplantation in Treating Patients with Recurrent Non-Hodgkin’s LymphomaBiological: aldesleukin, Biological: filgrastim, Drug: cyclophosphamide, Drug: etoposide, Radiation: radiation therapy, Procedure: peripheral blood stem cell transplantation, Procedure: bone marrow ablation with stem cell supportOverall survival, Disease-free survival, Frequency, and severity of toxicity associated with post-transplant aldesleukin therapyNational Cancer Institute (NCI)Phase 3206NCT00002649 (https://ClinicalTrials.gov/show/NCT01800071, Accessed on 22 March 2023)
8.A Phase Ib Trial of MVA-EBNA1/LMP2 Vaccine in Nasopharyngeal CarcinomaDrug: MVA-EBNA1/LMP2 vaccineImmune response to three cycles of MVA-EBNA1/LMP2 vaccine, Occurrence of adverse events defined according to NCI CTCAE version 4.02, Immune memory, and recall response to MVA-EBNA1/LMP2 vaccination, Measurement of EBV genome levels in plasma before, during and after vaccination, Tumor response as determined by Immune-Related Response Criteria (irRC)Cancer Research UKPhase 122NCT01800071 (https://ClinicalTrials.gov/show/NCT01800071, Accessed on 22 March 2023)
(viii) HIV
1.Prospective Evaluation of Etravirine for HIV-infected Patients in Need of Lipid-lowering DrugsDrug: stop statin and switch to an antiretroviral drug with less impact on lipid metabolismThe proportion of patients not qualifying anymore for statin treatment, fasting lipids changesCalmy Alexandra, Janssen-Cilag A.G., Switzerland, University Hospital, GenevaPhase 334NCT01543035 (https://ClinicalTrials.gov/show/NCT01543035, Accessed on 22 March 2023)
2.Behavioral Drug and HIV Risk Reduction counselling in Methadone Patients in ChinaBehavioral: Behavioral Drug and HIV Risk Reduction Counselling (BDRC), Behavioral: Drug counsellingReductions of illicit opiate use, Reductions in HIV risk behaviorsYale University, National Institute on Drug Abuse (NIDA)Phase 345NCT00757744 (https://ClinicalTrials.gov/show/NCT00757744, Accessed on 22 March 2023)
3.Positive Change Agents Program-Tanzania (Evaluation)Behavioral: Appreciative Inquiry Change Agents (CA) program (NAMWEZA)HIV Testing or other related services for network members of HIV Positive change agents, Depressive symptomsHarvard School of Public Health (HSPH), Harvard Medical School (HMS and HSDM), Muhimbili University of Health and Allied Sciences, Centres for Disease Control and PreventionPhase 31046NCT01693458 (https://ClinicalTrials.gov/show/NCT01693458, Accessed on 22 March 2023)
4.Safety and Efficacy of Switching from Regimens of ABC/3TC + a third Agent to E/C/F/TAF Fixed-Dose Combination (FDC) in Virologically Suppressed HIV 1 Infected AdultsDrug: E/C/F/TAF, Drug: ABC/3TC, Drug: Third Antiretroviral AgentPercentage of Participants Who Have HIV1 RNA < 50 Copies/mL as Defined by the FDA Snapshot Algorithm at Week 24, Change from Baseline in CD4+ Cell Count at Week 48Gilead SciencesPhase 3275NCT02605954 (https://ClinicalTrials.gov/show/NCT02605954, Accessed on 22 March 2023)
5.Using Drug Levels in the Blood to Guide Therapy in HIV Infected Patients Taking a Protease InhibitorProcedure: Therapeutic Drug Monitoring (TDM)Change in log10 plasma HIV1 RNA concentration from Step 2 entry (Week 4) to Week 24 (20 weeks postrandomization), change in log10 plasma HIV1 RNA concentration from study entry to Week 24 (20 weeks post-randomization)National Institute of Allergy and Infectious Diseases (NIAID)Phase 3360NCT00041769 (https://ClinicalTrials.gov/show/NCT00041769, Accessed on 22 March 2023)
6.Maraviroc is an Immunomodulatory Drug for Antiretroviral-treated HIV Infected Patients Exhibiting Immunologic FailureDrug: Placebo, Drug: MaravirocWeek 24 Change in Percentage of CD8+ T Cells That Co-express CD38 and HLA DR (Week 24 %CD38+HLA-DR+ CD8+ T Cells Minus Baseline %CD38+HLA-DR+ CD8+ T Cells), Change in CD4+ T Cell Count, Change in Ultrasensitive Plasma HIV RNA Level (Single Copy/mL Assay), Change in Brachial Artery Flow-mediated Dilatation (UCSF Site Only), Change in Gut-associated Lymphoid Tissue HIV RNA Level (UCSF Site Only)University of California, San Francisco, Pfizer, amfAR, The Foundation for AIDS Research, Stanford University, Case Western Reserve University, Rush UniversityPhase 445NCT00735072 (https://ClinicalTrials.gov/show/NCT00735072, Accessed on 22 March 2023)
7.Anti-HIV Drug Regimens with or Without Protease Inhibitors and Drug Level Monitoring in HIV Infected AdolescentsDrug: Efavirenz + 2 NRTIs, Drug: Lopinavir/Ritonavir + 2 NRTIs, Procedure: Therapeutic Drug MonitoringThe proportion of patients achieving viral suppression (viral load less than 1,000 copies/mL) at Week 24 and maintaining suppression through Week 48 while remaining on study treatment, the proportion of patients achieving virologic suppression (viral load less than 1,000 copies/mL) at Week 24 and maintaining suppression through Week 96 while remaining on study treatment, CD4 (T helper cells), CD8 (cytotoxic T cells), naive CD4 T cells (CD62L/CD45RA/CD4), and activated CD8 T cells (HLA-DR/CD38/CD8), changes from baseline to Weeks 24, 48, and 96 for percentage and total number of CD19 (B cells), total T cells (CD3 T cells), CD4 (T helper cells), CD8 (cytotoxic T cells), naive CD4 T cells (CD62L/CD45RA/CD4), and activated CD8 T cells (HLA-DR/CD38/CD8)National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)Phase 3240NCT00075907 (https://ClinicalTrials.gov/show/NCT00075907, Accessed on 22 March 2023)
8.Drug Interaction Study Between Lumefantrine and Lopinavir/RitonavirDrug: Lumefantrine - lopinavir/ritonavir drug interaction, Drug: Lumefantrine only arm Makerere University, University of LiverpoolPhase 432NCT00619944 (https://ClinicalTrials.gov/show/NCT00619944, Accessed on 22 March 2023)
9.Antidepressant Medication for Reducing HIV Risk Behavior in Depressed Intravenous Drug UsersDrug: Antidepressant MedicationMaintenance of HIV risk-free drug behavior (measured at Month 12), Reduction in depressive symptoms (measured at Month 12)Butler Hospital, National Institute of Mental Health (NIMH)Phase 3265NCT00228007 (https://ClinicalTrials.gov/show/NCT00228007, Accessed on 22 March 2023)
10.Drug Interaction Study of Famotidine and Atazanavir with Ritonavir in HIV-Infected PatientsDrug: Atazanavir/Ritonavir, Drug: Atazanavir/Ritonavir + Famotidine, Drug: Atazanavir/Ritonavir + Tenofovir Disoproxil Fumarate + Famotidine Bristol-Myers SquibbPhase 440NCT00384904 (https://ClinicalTrials.gov/show/NCT00384904, Accessed on 22 March 2023)
a

“Completed” status here means the study has ended and participants are no longer being examined or treated; that is, the last participant’s last visit has occurred.

5. Current Vaccines for Viral Oncogenesis Therapeutics

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Over the past few decades, tumor immunotherapy research has advanced significantly, with many trials now being evaluated in clinical settings. Cancer vaccination is a potential treatment approach for immunizing tumor cells. Tumor antigens from cancer vaccines, which may be given as entire cells, peptides, nucleic acids, etc., induce antitumor immunity. Optimal cancer vaccines stimulate humoral and cellular immunity while overcoming tumor-induced immune suppression. (330) Cancer vaccines vary from conventional vaccinations since their therapeutic goals involve using cellular immune responses specific to tumor antigens to destroy tumor cells. The hepatitis B virus and human papillomavirus are the only preventive vaccinations currently used to prevent virally induced cancers. (331) Tumor antigens are also endogenous with limited immunogenicity in contrast to conventional vaccinations that contain antigens from foreign infections. It can be challenging to get the immune system to respond properly to tumor antigens. (332) Traditional vaccinations also promote humoral immunity. Nevertheless, eliminating malignant cells for cancer vaccines depends on CD8+ cytotoxic T cell-mediated cellular immunity. (333)
Cancer vaccines fall into four categories, viz, nucleic acid-based vaccinations, viral-based vaccines, peptide-based vaccines, and cell-based vaccines. Initially, cancer vaccines take the form of cell-based vaccinations. Cell-based cancer vaccines elicit a larger immune response to antigens since they are frequently made from whole or fragmented cells that include tumor antigens. The dendritic cells (DC) vaccine is a crucial subset of cell-based vaccinations. Clinical trials of customized neoantigen cancer vaccines focused on DC have revealed positive antitumor outcomes. However, the creation of DC vaccines is constrained by laborious procedures and high expenses. Viral genetic material can be altered to include sequences containing tumor antigens since viruses are naturally immunogenic. Adenovirus is one of several recombinant viruses that can spread infection via immune cells. (330)

5.2.1. Mechanism of Cancer Vaccines

Optimal interactions between immunological and nonimmune components of the tumor microenvironment (TME) are necessary for effective antitumor immunity. Antigen-presenting cells (APCs), namely dendritic cells (DCs), capture and cross-present the antigens released by tumor cells and activate T cells. (334) In the TME, natural killer (NK) cells, neutrophils, and macrophages of the innate immune system are extremely important for the immediate recognition and attack of tumor cells. When tumor cells undergo immunogenic cell death (ICD)─spontaneously or because of therapies such as some forms of chemotherapy─they emit molecular patterns linked with risk. As a result, DCs develop, take up, process, and present antigens on MHC class I (MHC-I) and MHC-II molecules (via antigen cross-presentation). (335) These DCs go to secondary lymphoid organs where they bind MHC-T cell receptors and coreceptors to connect with naïve CD4+ T cells and CD8+ T cells. To prime T cells, migratory DCs also pick up antigens in the tumor microenvironment or the periphery and ″transfer″ them to lymph node-resident DCs. (336) It is significant to highlight that the activation of CD8+ T cells and tumor immunity depend heavily on CD4+ T cell support. T cell stemness is becoming increasingly important as a regulator of tumor immunity and a determinant of the immunotherapy response. After cognate contacts, the activated T cells return to the TME to limit tumor development by direct killing and IFN-mediated inhibition of cancer cell proliferation. (337)

5.2.3. Current Vaccines and Their Effectiveness

Efforts toward vaccine development have been gaining immense attention. One of the vaccines, the gp350-Ferritin Nanoparticle Vaccine, has been developed for infection with the Epstein–Barr virus (EBV), which is linked to several human disorders, notably infectious mononucleosis (IM) as well as several types of cancers. Neoplasms following infection include stomach and nasopharyngeal carcinoma, Burkitt and Hodgkin lymphoma, and lymphoproliferative diseases. The likelihood that an EBV vaccination will improve public health is highlighted by the incidence and severity of these disorders. (338) A murine monoclonal antibody (mAb) named 72A1 potently neutralizes EBV infections of B cells, (339) and its anticipated epitope on gp350 closely resembles the anticipated binding site of CR2, pointing to a method of neutralization mediated by this antibody. (340) According to Ogembo et al. (2013), the mAb 72A1 prevents gp350 from interacting with CR1, further demonstrating the functional importance of this epitope and making it a desirable vaccine target to stop viral infection of B cells, the primary target cell type of EBV. (341) The researcher has taken gp350 into account to prevent EBV-linked disorders and thus developed a gp350-Ferritin Nanoparticle Vaccine.
Similarly, Interleukin 12 (IL-12) Vaccines have been developed because of the pivotal role of IL-12 in cancer immunotherapy. Interleukin 12 (IL-12) is a pleiotropic (affecting multiple unrelated organs) cytokine whose effects link to innate and adaptive immunity. IL-12 was initially identified as a substance released by B-cell lines that had undergone EBV transformation in response to PMA. IL-12 was initially known as the ″cytotoxic lymphocyte maturation factor″ (342) and ″natural killer cell stimulatory factor″ (343) based on its effects. IL-12 seems to be an excellent option for cancer immunotherapy in humans due to its ability to integrate both adaptive and innate immunity and potently stimulate the production of IFNs, a cytokine that coordinates natural processes of anticancer defense. (344) However, the highly limited therapeutic efficacy of this cytokine and the severe adverse effects connected with the systemic injection of IL-12 in research studies significantly reduced excitement for its use in cancer patients.
Notwithstanding these hurdles, clinical oncology is still very interested in IL-12. The current review analyzes clinical trials focusing on ongoing investigations to increase the treatment effectiveness of IL-12 and reduce its toxicity. It also reviews the much more promising IL-12-based techniques in animal models. (345) Moreover, IL-12 has been demonstrated to be highly efficient in animal models of tumor treatment due to its ability to promote various direct and indirect anticancer actions related to innate immunity, adaptive immunity, and nonimmune pathways. Many mouse models, including tumor cells and hematologic malignancies comprising low immunogenic tumors, have effectively used this. (345−350) The anticancer effects of IL-12 have been amplified in several efforts. Combining IL-12 with numerous treatment modalities, including chemotherapeutics, cytokines, antibodies, antiangiogenic drugs, radiation, adoptive therapy, and tumor vaccines, can significantly increase its antitumor effectiveness. (345)
Many gene therapeutic techniques have been developed, permitting local and extended cytokine production to decrease IL-12-induced toxicities further and enhance its efficiency in experimental tumor treatment. The IL-12 gene has been inserted into a variety of viral (351−355) and nonviral (356−358) vectors, into developing tumors, (357,359−361) or into fibroblasts designed to express IL-12 that have been injected at the location of an existing tumor. (345) Vaccines containing tumor antigens, (362) tumor cells, (351,352) and dendritic cells (363−365) have also been developed effectively using the IL-12 gene. Moreover, IL-12 has improved the anti-cancer effects of adoptive therapies using IL-12-secreting specific T cells (366) or Herpes simplex virus. (367) Many vaccines have been developed against oncogenic viruses for potential therapeutics, summarized in Table 4.
Table 4. Available Potential Vaccines against Oncogenic Viruses
S. No.VirusesVaccinesReferences
1.Hepatitis B virus (HBV)Engerix-B and Recombivax HBHEPLISAV-B (368)
2.Human Papilloma Virus (HPV)Gardasil (a bivalent HPV vaccine), Cervarix (368)
3.Kaposi sarcoma herpesvirus (KSHV/HHV-8)Epitopes-based vaccines mRNA-based vaccines (Potential candidates) (369,370)
4.Epstein–Barr virus (EBV/HHV-4)EBV gp350-Ferritin nanoparticle vaccine (Under trials) (371)
5.Merkel cell polyomavirus (MCPyV)A VP1-target vaccine formulated with CRA (Potential candidate), Interleukin-12 (IL-12) Plasmid Vaccines (372,373,374)
6.Hepatitis C virus (HCV)New Hepatitis C Prophylactic Vaccine (Under trials) (375)
7.Human T-cell leukemia/ Lymphotropic virus-1 (HTLV-1)TAX protein-based epitopes vaccine peptide-based vaccine (HBZ peptide) (Potential candidates) (376,377)
8.Human immunodeficiency virus (HIV)BG505 MD39.3, BG505 MD39.3 gp151, and BG505 MD39.3 gp151 CD4KO HIV Trimer mRNA Vaccines (378)

6. Challenges Associated with Antivirals during Viral Oncogenesis

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The interplay of certain oncoviruses and the onset of cancer has become definitive in recent times. With an approximate value of 15–20% of various human cancers being caused by such oncoviruses, it has raised a medical concern all over the globe. The onset of cancer cannot be concluded on the basis of single or limited aspects *indeed many factors could be involved. (3,89) The general mechanism followed by cancer-causing viruses was reported to be mediated by disrupting the tumor suppressor gene, p53, and retinoblastoma, pRb. (8) Scientists have been on the verge of developing treatment modalities to treat such virus-induced oncogenesis. Antivirals are considered to be the most common treatment modality to treat viral infections. Still, the rapidly changing and evolving nature of viruses makes it challenging to develop antivirals that could be effective against viral oncogenesis every time. (379)
Antiviral therapy for EBV-induced tumors includes acyclovir, famciclovir, and ganciclovir, which play potential inhibitory role against EBV replication during the lytic phase. (249) The main mechanism behind the functioning of EBV-based antivirals depends on the activation of lytic phase-associated kinases, which convert the antiviral’s inactive form to its active form. With this conversion, the level of viral replication is lowered, eventually destroying virus-induced tumor cells. The challenge behind this strategy can be seen during the lytic phase induction of EBV. (380) Further the induction poses a high risk of circulation and distribution of viral particles within the host. (381)
Similarly, antiviral therapy for HHV-8-induced sarcoma, includes Ganciclovir and Valganciclovir, which plays an important role in the inhibition of HHV-8 replication in a trial encompassing 26 HHV-8-infected patients. (382,383) With the eventual administration of ganciclovir, the serum levels of HHV-8 were reported to get reduced. However, recent clinical studies using valganciclovir showed that the potential of inhibition seems to have reduced. (384) Cidofovir administration showed no reduction in HHV-8 viral loads in the plasma; thus, it may not show clear evidence about the effect of antivirals concerning HHV-8-associated infection. (385) In recent times, siRNA-based antivirals have gained a great deal of importance. Studies have documented the potent knockdown potential of siRNA against disease-associated factors. (386) siRNA is potent against HBV, HPV, and HCV. (387) However, certain shortcomings are found in current research, such as runoff of virus, inadequate uptake by cells, reduced stability, adverse effects around nonspecific targets, and immune levels elevation. (388) Compounds such as lamivudine, adefovir, emtricitabine, entecavir, and telbivudine are potent inhibitors of HBV replication in cell lines. Toxic effects on lactic acid levels and metabolism, severe liver illness, and, in rare cases, genotypic and phenotypic resistance exhibited by the virus strain after treatment halted further development of such drugs. (389) Although there are no medicines available for selective antiviral for HPV, however, several nonselective methods are in use. (390) Moreover, DNA helicase, the sole molecular target, may seem promising for inhibitor development, even though it has been found difficult to produce and establish in experiments. The viral polymerase NS5b, protease NS3/4a, and helicase NS3 are attractive targets in HCV. The virus internal ribosome entry site (IRES), antisense inhibition, and the NS2 zinc-dependent protease have limited targets that might be studied for improved treatment outcomes. Despite the potency of NNRTI inhibitors of HCV polymerase, may block a fraction of the six HCV strains, thus limiting their usefulness. (391,392) There are three types of viral polymerase inhibitors used to treat HIV infection: (i) nucleoside reverse transcriptase inhibitors (NRTIs) (such as zidovudine, lamivudine, and abacavir), (ii) nucleotide reverse transcriptase inhibitors (NtRTIs), (of which tenofovir is the only approved one) and (iii) non-nucleoside reverse transcriptase inhibitors (NNRTIs). HIV inhibitors, whether NRTIs, NNRTIs, and protease inhibitors (PIs), or fusion inhibitors (FIs) (like Enfuvirtide), have had their efficacy severely curtailed by the rapid development of resistance and unwanted side effects. (391,392)
Resistance development and toxin generation are likely constrained by other viral processes such as fusion, viral coreceptor, and integration. (393) It is tempting to speculate that certain anti-HIV1 medications targeting HIV1 RT would also be efficacious against HTLV1 RT because RNA reverse transcription is required to replicate both HIV1 and HTLV1 retroviruses. Both RTs are closely linked with the evolutionary tree. Indeed, it was proven in cell-to-cell transmission studies that AZT, 3TC, carbocyclic phosphonate 2′-oxa-3′-aza-nucleoside, and tenofovir inhibited HTLV1 transmission. (394−397) Although, in recent findings, no immunological or clinical responses were seen other than some modest reductions in HTLV1 PVL were observed. (184) In addition, further evidence revealed that AZT, regardless of the viral conditions of treated cells, might block telomerase and lead to cell death. The fact that HTLV1 is transmitted almost exclusively through cell-to-cell contact may further reduce the effectiveness of AZT and other NRTIs in combating the virus. (184) Adefovir dipivoxil and tenofovir disoproxil are significantly more effective than AZT in reducing HTLV1 cell-to-cell transmission.

7. Future Perspectives and Concluding Remarks

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A viral infection heavily influences the global cancer burden, and these viruses are becoming a leading cause of death and life-threatening diseases. (398) Indeed, human tumor virology has attracted a great deal of interest in recent years. Oncogenic viruses have used various strategies to hijack the cellular pathways required for carcinogenesis. With the advent of technologies and systems-level studies, the concepts and practice of cancer treatment prevention have been revolutionized. For some oncogenic viruses, there is still a lack of convenient, effective antiviral agents that can be used for primary prevention. Therefore, despite the advances in delivering effective antiviral therapies, the currently available antiviral medications have many concerns, including high costs, drug resistance, safety concerns, and efficacy limits. (398,399)
Translation inhibitors have shown some success in targeting cancer cells. It is profitable to create drugs targeting many translation-related proteins. The challenge lies in targeting these inhibitors precisely to cancer cells. The vast array of proteins at play will provide drug designers with endless opportunities for targeted therapy. (400−402) Researchers have developed some highly specific, safe, and effective cancer therapies that inhibit translation; this field of inhibitor development will likely continue for a long time due to newly discovered targets and our ever-increasing knowledge of the biological basics of these processes.
Nature has been a vital source of medical products and novel antiviral agents for ages. Studies have shown that secondary metabolites derived from various insects, marine organisms, microbes, and medicinal plants effectively prevent cancer patients infected with a virus. (403−405) In contrast to combinatorial synthesized compounds, these natural bioactive compounds show excellent biochemical specificity against a wide range of molecular targets, while being absorbed and digested with minimal toxicity. Furthermore, it is well known that eating a diet rich in antioxidants has health benefits. Cancer therapies like chemotherapy and radiation therapy have various adverse effects, necessitating complementary medicine to treat cancer. (406−409) Nowadays, two or more cancer therapies are usually administered to reduce the risk of acquiring resistance. Immunotherapy and oncological viral therapies, which use the patient’s immune system to attack cancer cells, are the latest additions to cancer treatment strategies. With advanced techniques, future research should be focused on efficiently separating and identifying valuable bioactive components from the chemically diversified natural product extracts, which can be employed in drug development. Moreover, these natural substances can be recommended to rural and underprivileged people to cure cancers since they are less costly and have virtually no side effects. (406−409)
In conclusion, future research activities should continually improve the understanding of the relationship between the dynamics of viruses and the natural history of diseases. These efforts could add to our arsenal of antivirals against these viruses and yield promising outcomes in adjuvant therapy for viral oncogenesis. Additionally, the failure of drugs in human trials is a general phenomenon that must be examined and addressed.

Data Availability

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Not Applicable.

Author Information

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  • Corresponding Authors
    • Janne Ruokolainen - Department of Applied Physics, School of Science, Aalto University, 02150 Espoo, Finland;  Email: [email protected]
    • Kavindra Kumar Kesari - Department of Applied Physics, School of Science, Aalto University, 02150 Espoo, Finland;  Division of Research and Development, Lovely Professional University, Phagwara 144411, Punjab, India;  Orcidhttps://orcid.org/0000-0003-3622-9555;  Email: [email protected]
    • Piyush Kumar Gupta - Department of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Greater Noida 201310, Uttar Pradesh, India;  Department of Biotechnology, Graphic Era Deemed to Be University, Dehradun 248002, Uttarakhand, India;  Faculty of Health and Life Sciences, INTI International University, Nilai 71800, Malaysia;  Orcidhttps://orcid.org/0000-0002-3346-910X;  Email: [email protected]
  • Authors
    • Shivam Chowdhary - Department of Industrial Microbiology, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj 211007, Uttar Pradesh India
    • Rahul Deka - Department of Bioengineering and Biotechnology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India
    • Kingshuk Panda - Department of Applied Microbiology, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India
    • Rohit Kumar - Department of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Greater Noida 201310, Uttar Pradesh, India
    • Abhishikt David Solomon - Department of Molecular & Cellular Engineering, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj 211007, Uttar Pradesh, India
    • Jimli Das - Centre for Biotechnology and Bioinformatics, Dibrugarh University, Assam 786004, India
    • Supriya Kanoujiya - School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
    • Ashish Kumar Gupta - Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110029, India
    • Somya Sinha - Department of Biotechnology, Graphic Era Deemed to Be University, Dehradun 248002, Uttarakhand, India
  • Author Contributions

    Shivam Chowdhary – Writing – Original draft, Review & Editing, Artwork. Rahul Deka - Writing – Original draft, Review & Editing, Artwork. Kingshuk Panda – Review & Editing, Artwork. Rohit Kumar – Review & Editing, Artwork. Abhishikt David Solomon – Review & Editing, Artwork. Jimli Das – Review & Editing, Artwork. Supriya Kanoujiya – Review & Editing. Ashish Kumar Gupta – Review & Editing. Somya Sinha – Review & Editing. Janne Ruokolainen – Conceptualization, Visualization, Project administration. Kavindra Kumar Kesari – Conceptualization, Visualization, Project administration. Piyush Kumar Gupta – Conceptualization, Visualization, Project administration.

  • Funding

    Any organizations for this work supported no funding.

  • Notes
    This article does not contain any studies with human or animal subjects.
    The authors declare no competing financial interest.

Acknowledgments

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Dr. Piyush Kumar Gupta is thankful to the Department of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Greater Noida, India, for providing the infrastructure and research facilities.

References

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    Viruses encounter many challenges within host cells in order to replicate their nucleic acid. In the case of DNA viruses, one challenge that must be overcome is recognition of viral DNA structures by the host DNA damage response (DDR) machinery. This is accomplished in elegant and unique ways by different viruses as each has specific needs and sensitivities dependent on its life cycle. In this review, we focus on three DNA tumor viruses and their interactions with the DDR. The viruses Epstein-Barr virus (EBV), Kaposi's sarcoma-assocd. herpesvirus (KSHV), and human papillomavirus (HPV) account for nearly all of the virus-assocd. human cancers worldwide. These viruses have also been excellent models for the study of oncogenic virus-mediated cell transformation. In this review, we will discuss how each of these viruses engage and subvert aspects of the host DDR. The first level of DDR engagement is a result of the genetic linkage between the oncogenic potential of these viruses and their ability to replicate. Namely, the promotion of cells from quiescence into the cell cycle to facilitate virus replication can be sensed through aberrant cellular DNA replication structures which activate the DDR and hinder cell transformation. DNA tumor viruses subvert this growth-suppressive DDR through changes in viral oncoprotein expression which ultimately facilitate virus replication. An addnl. level of DDR engagement is through direct detection of replicating viral DNA. These interactions parallel those obsd. in other DNA virus systems in that the need to subvert these intrinsic sensors of aberrant DNA structure in order to replicate must be in place. DNA tumor viruses are no exception. This review will cover the mol. features of DNA tumor virus interactions with the host DDR and the consequences for virus replication.
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    Tornesello, M. L.; Annunziata, C.; Tornesello, A. L.; Buonaguro, L.; Buonaguro, F. M. Human Oncoviruses and P53 Tumor Suppressor Pathway Deregulation at the Origin of Human Cancers. Cancers 2018, Vol. 10, Page 213 2018, 10 (7), 213,  DOI: 10.3390/cancers10070213
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    Krump, N. A.; You, J. Molecular Mechanisms of Viral Oncogenesis in Humans. Nat. Rev. Microbiol. 2018 1611 2018, 16 (11), 684– 698,  DOI: 10.1038/s41579-018-0064-6
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    Lambert, P. F.; Sugden, B. Cancer Issue: Viruses and Human Cancer. Yale J. Biol. Med. 2006, 79 (3–4), 115,  DOI: 10.1016/B978-0-323-47674-4.00012-8
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    Ezirganli, S.; Kazancioglu, H. O.; Acar, A. H.; Ozdemir, H.; Kuzu, E.; Inan, D. S. Effects of Ankaferd Bloodstopper on Bone Healing in an Ovariectomized Osteoporotic Rat Model. Exp. Ther. Med. 2017, 13 (5), 1827– 1831,  DOI: 10.3892/etm.2017.4166
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    10
    Effects of Ankaferd BloodStopper on bone healing in an ovariectomized osteoporotic rat model
    Ezirganli, Seref; Kazancioglu, Hakki Oguz; Acar, Ahmet Huseyin; Ozdemir, Hakan; Kuzu, Emre; Inan, Deniz Sahin
    Experimental and Therapeutic Medicine (2017), 13 (5), 1827-1831CODEN: ETMXA2; ISSN:1792-1015. (Spandidos Publications Ltd.)
    Bone defects resulting from oncol. surgical resections, congenital facial anomalies, trauma or infection represent a significant and common clin. problem. The present study aimed to evaluate the effects of a com.-available medicinal plant ext. product, Ankaferd BloodStopper (ABS), on bone healing. The present study was performed on 24 female ovariectomized (OVX) rats. A defect on each rat calvarium was created using a trephine burr prior to the rats being divided into two groups. Defects were grafted with a gelatin sponge soaked with normal saline (control group) or plant ext. (exptl. group). Half of the animals were sacrificed after 2 wk and the others after 4 wk. In the control group, the defects were not filled with regenerated bone. By contrast, in the exptl. group, all defect areas had an increased amt. of regenerated bone and connective tissue. Osteoblastic activity appeared to be greater in the exptl. group however, osteoclastic activity was obsd. to be higher in the control group. At 2 and 4 wk, there was a significant difference in the amt. of newly regenerated bone obsd. in the exptl. group compared with the control group (P<0.05). Therefore, the results of the present study indicated that local ABS application had a pos. effect on bone healing in the OVX rat model.
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    Papastergiou, V.; Lombardi, R.; MacDonald, D.; Tsochatzis, E. A. Global Epidemiology of Hepatitis B Virus (HBV) Infection. Curr. Hepat. Rep. 2015, 14 (3), 171– 178,  DOI: 10.1007/s11901-015-0269-3
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    Jiang, B.; Hildt, E. Intracellular Trafficking of HBV Particles. Cells 2020, Vol. 9, Page 2023 2020, 9 (9), 2023,  DOI: 10.3390/cells9092023
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    Liang, T. J. Hepatitis B: The Virus and Disease. Hepatology 2009, 49 (S5), S13– S21,  DOI: 10.1002/hep.22881
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    Hepatitis B: the virus and disease
    Liang, T. Jake
    Hepatology (Hoboken, NJ, United States) (2009), 49 (5, Suppl.), S13-S21CODEN: HPTLD9; ISSN:0270-9139. (John Wiley & Sons, Inc.)
    A review. Hepatitis B virus (HBV) infects more than 300 million people worldwide and is a common cause of liver disease and liver cancer. HBV, a member of the Hepadnaviridae family, is a small DNA virus with unusual features similar to retroviruses. HBV replicates through an RNA intermediate and can integrate into the host genome. The unique features of the HBV replication cycle confer a distinct ability of the virus to persist in infected cells. Virol. and serol. assays have been developed for diagnosis of various forms of HBV-assocd. disease and for treatment of chronic hepatitis B infection. HBV infection leads to a wide spectrum of liver disease ranging from acute (including fulminant hepatic failure) to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Acute HBV infection can be either asymptomatic or present with symptomatic acute hepatitis. Most adults infected with the virus recover, but 5%-10% are unable to clear the virus and become chronically infected. Many chronically infected persons have mild liver disease with little or no long-term morbidity or mortality. Other individuals with chronic HBV infection develop active disease, which can progress to cirrhosis and liver cancer. These patients require careful monitoring and warrant therapeutic intervention. Extrahepatic manifestations of HBV infection are rare but can be difficult to diagnose and manage. The challenges in the area of HBV-assocd. disease are the lack of knowledge in predicting outcome and progression of HBV infection and an unmet need to understand the mol., cellular, immunol., and genetic basis of various disease manifestations assocd. with HBV infection.
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    Jiang, B.; Himmelsbach, K.; Ren, H.; Boller, K.; Hildt, E. Subviral Hepatitis B Virus Filaments, like Infectious Viral Particles, Are Released via Multivesicular Bodies. J. Virol. 2016, 90 (7), 3330– 3341,  DOI: 10.1128/JVI.03109-15
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    14
    Subviral hepatitis B virus filaments, like infectious viral particles, are released via multivesicular bodies
    Jiang, Bingfu; Himmelsbach, Kiyoshi; Ren, Huimei; Boller, Klaus; Hildt, Eberhard
    Journal of Virology (2016), 90 (7), 3330-3341CODEN: JOVIAM; ISSN:1098-5514. (American Society for Microbiology)
    In addn. to infectious viral particles, hepatitis B virus-replicating cells secrete large amts. of subviral particles assembled by the surface proteins, but lacking any capsid and genome. Subviral particles form spheres (22-nm particles) and filaments. Filaments contain a much larger amt. of the large surface protein (LHBs) compared to spheres. Spheres are released via the constitutive secretory pathway, while viral particles are ESCRT-dependently released via multivesicular bodies (MVBs). The interaction of virions with the ESCRT machinery is mediated by α-taxilin that connects the viral surface protein LHBs with the ESCRT component tsg101. Since filaments in contrast to spheres contain a significant amt. of LHBs, it is unclear whether filaments are released like spheres or like virions. To study the release of subviral particles in the absence of virion formation, a core-deficient HBV mutant was generated. Confocal microscopy, immune electron microscopy of ultrathin sections and isolation of MVBs revealed that filaments enter MVBs. Inhibition of MVB biogenesis by the small-mol. inhibitor U18666A or inhibition of ESCRT functionality by coexpression of transdominant neg. mutants (Vps4A, Vps4B, and CHMP3) abolishes the release of filaments while the secretion of spheres is not affected. These data indicate that in contrast to spheres which are secreted via the secretory pathway, filaments are released via ESCRT/MVB pathway like infectious viral particles.
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    Cai, D.; Yan, R.; Xu, J. Z.; Zhang, H.; Shen, S.; Mitra, B.; Marchetti, A.; Kim, E. S.; Guo, H. Characterization of the Termini of Cytoplasmic Hepatitis B Virus Deproteinated Relaxed Circular DNA. J. Virol. 2020, 95 (1), e00922,  DOI: 10.1128/JVI.00922-20
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    Nassal, M. Hepatitis B Viruses: Reverse Transcription a Different Way. Virus Res. 2008, 134 (1–2), 235– 249,  DOI: 10.1016/j.virusres.2007.12.024
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    Hepatitis B viruses: Reverse transcription a different way
    Nassal, Michael
    Virus Research (2008), 134 (1-2), 235-249CODEN: VIREDF; ISSN:0168-1702. (Elsevier B.V.)
    A review. Hepatitis B virus (HBV), the causative agent of B-type hepatitis in humans, is the type member of the Hepadnaviridae, hepatotropic DNA viruses that replicate via reverse transcription. Beyond long-established differences to retroviruses in gene expression and overall replication strategy newer work has uncovered addnl. distinctions in the mechanism of reverse transcription per se. These include protein-priming by the unique extra terminal protein domain of the reverse transcriptase (RT) utilizing an RNA hairpin for de novo initiation of first strand DNA synthesis, and the strict dependence of this process on cellular chaperones. Recent in vitro reconstitution systems enabled first biochem. insights into this multifactorial reaction, complemented by high resoln. structural information on the RNA, though not yet the protein, level. Genetic approaches have revealed long-distance interactions in the nucleic acid templates as an important factor enabling the puzzling template switches required to produce the relaxed circular (RC) DNA found in infectious virions. Finally, the failure of even potent HBV RT inhibitors to eliminate nuclear covalently closed circular (ccc) DNA, the functional equiv. of integrated proviral DNA, has spurred a renewed interest in the mechanism of cccDNA generation. These new developments are in the focus of this review.
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    Ji, J.; Xu, X.; Wu, Q.; Wang, X.; Li, W.; Yao, L.; Kan, Y.; Yuan, L.; Bi, Y.; Xie, Q. Simple and Visible Detection of Duck Hepatitis B Virus in Ducks and Geese Using Loop-Mediated Isothermal Amplification. Poult. Sci. 2020, 99 (2), 791– 796,  DOI: 10.1016/j.psj.2019.12.024
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    17
    Simple and visible detection of duck hepatitis B virus in ducks and geese using loop-mediated isothermal amplification
    Ji, Jun; Xu, Xin; Wu, Qianqian; Wang, Xueyu; Li, Wanyu; Yao, Lunguang; Kan, Yunchao; Yuan, Lu; Bi, Yingzuo; Xie, Qingmei
    Poultry Science (2020), 99 (2), 791-796CODEN: POSCAL; ISSN:1525-3171. (Elsevier Inc.)
    In this study, loop-mediated isothermal amplification (LAMP) was used to establish a rapid, specific, and visual detection method for duck hepatitis B virus (DHBV). The design and synthesis of 4 specific LAMP primers were based on the conserved gene region of the DHBV genome, and the optimum temp. and time of the LAMP reaction were 63°C and 50 min, resp. The LAMP assay was confirmed to be specific for DHBV detection and had the same sensitivity as the quant. PCR assay. A visual detection method for rapid detn. of results was developed using a color indicator contg. phenol red and cresol red. A color change was produced based on a pH change in the reaction system, indicating a pos. reaction. For the detection of samples from ducks and geese, the LAMP method has the advantages of simplicity, high sensitivity and specificity, good visibility, and low cost. Moreover, it is more practical and convenient than PCR-related assays for the clin. detection of DHBV.
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  18. 18
    He, X.; Xu, H.; Wang, X.; Wu, J.; Niu, J.; Gao, P. Associations between the Single Nucleotide Polymorphisms of APOBEC3A, APOBEC3B and APOBEC3H, and Chronic Hepatitis B Progression and Hepatocellular Carcinoma in a Chinese Population. Mol. Med. Rep. 2019, 20 (3), 2177– 2188,  DOI: 10.3892/mmr.2019.10455
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    18
    Associations between the single nucleotide polymorphisms of APOBEC3A, APOBEC3B and APOBEC3H, and chronic hepatitis B progression and hepatocellular carcinoma in a Chinese population
    He, Xiuting; Xu, Hongqin; Wang, Xiaomei; Wu, Jing; Niu, Junqi; Gao, Pujun
    Molecular Medicine Reports (2019), 20 (3), 2177-2188CODEN: MMROA5; ISSN:1791-3004. (Spandidos Publications Ltd.)
    The present study examd. the relationships between the single nucleotide polymorphisms (SNPs) of three members of the apolipoprotein B mRNA-editing catalytic polypeptide-like 3 (A3) gene family, A3A, A3B and A3H, and hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) in a Han Chinese population. A total of 654 patients were enrolled in the study between Jan. 2012 and July 2016, including 104 patients with chronic HBV infection (CHB), 265 patients with HBV-related liver cirrhosis and 285 patients with HBV-related HCC. A total of two A3A SNPs (rs7286317 and rs7290153), three A3B SNPs (rs2267398, rs2267401 and rs2076109), and five A3H SNPs (rs56695217, rs139302, rs139297, rs139316 and rs139292) were genotyped using a MassArray system. Statistical anal. and haplotype estn. were conducted using Haploview and Unphased software. No significant assocns. were obsd. between the A3A, A3B and A3H SNPs and the development of CHB and HCC. Haplotype anal. revealed that the mutant haplotypes C-T-A, C-T-G, T-G-G and T-T-G from the A3B SNPs rs2267398-rs2267401-rs2076109 carried a lower risk of HCC than the ref. haplotype. These findings suggested that there was no relationship between A3A, A3B and A3H SNPs and CHB progression or HCC development in the Han Chinese population.
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    Kanda, T.; Goto, T.; Hirotsu, Y.; Moriyama, M.; Omata, M. Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review. Int. J. Mol. Sci. 2019, Vol. 20, Page 1358 2019, 20 (6), 1358,  DOI: 10.3390/ijms20061358
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    Slagle, B. L.; Bouchard, M. J. Role of HBx in Hepatitis B Virus Persistence and Its Therapeutic Implications. Curr. Opin. Virol. 2018, 30, 32– 38,  DOI: 10.1016/j.coviro.2018.01.007
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    20
    Role of HBx in hepatitis B virus persistence and its therapeutic implications
    Slagle, Betty L.; Bouchard, Michael J.
    Current Opinion in Virology (2018), 30 (), 32-38CODEN: COVUAF; ISSN:1879-6257. (Elsevier B.V.)
    A review. Chronic hepatitis B virus infection is a significant risk factor for cirrhosis and hepatocellular carcinoma. The HBx protein is required for virus replication, but the lack of robust infection models has hindered our understanding of HBx functions that could be targeted for antiviral purposes. We briefly review three properties of HBx: its binding to DDB1 and its regulation of cell survival and metab., to illustrate how a single viral protein can have multiple effects in a cell. We propose that different functions of HBx are needed, depending on the changing hepatocyte environment encountered during a chronic virus infection, and that these functions might serve as novel therapeutic targets for inhibiting hepatitis B virus replication and the development of assocd. diseases.
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    Kattan, S. W.; Nafie, M. S.; Elmgeed, G. A.; Alelwani, W.; Badar, M.; Tantawy, M. A. Molecular Docking, Anti-Proliferative Activity and Induction of Apoptosis in Human Liver Cancer Cells Treated with Androstane Derivatives: Implication of PI3K/AKT/MTOR Pathway. J. Steroid Biochem. Mol. Biol. 2020, 198, 105604,  DOI: 10.1016/j.jsbmb.2020.105604
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    21
    Molecular docking, anti-proliferative activity and induction of apoptosis in human liver cancer cells treated with androstane derivatives: Implication of PI3K/AKT/mTOR pathway
    Kattan, Shahad W.; Nafie, Mohamed S.; Elmgeed, Gamal A.; Alelwani, Walla; Badar, Muhammad; Tantawy, Mohamed A.
    Journal of Steroid Biochemistry and Molecular Biology (2020), 198 (), 105604CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)
    Worldwide, cancer is still an area with high unmet medical need. Lead optimization efforts towards structure-based drug design were employed to discover newly synthesized hetero-steroid derivs. with promising anticancer effects against hepatocellular carcinoma (HCC). The aim of our study is to evaluate the anti-proliferative activity and the mechanism, a dual PI3K/mTOR inhibitor, and mechanism of action of a series of heterocylic androstane derivs. as anti-HCC agent. The cytotoxic effects of different heterocylic androstanes and 5FU as single agents, were assessed against both HepG2 cells and Non-malignant MDCK cell line to assess the toxicity. Then the underlying mechanism of compd. 4 as most promising compd. was evaluated using mol. docking, MTT assay, cell cycle anal., DNA fragmentation, and real-time PCR. The results of MTT assay showed potential cytotoxic effect for compd. 4 and 5 against liver cancer cell line with IC50 value 39.81 and 57.54 μM, resp. Inhibition of the PI3K/AKT/mTOR pathway was achieved by compd. 4, which was documented by mol. docking and augmented by gene expression anal. Detailed mechanism revealed that compd. 4 induced cell cycle arrest, DNA fragmentation, and induction of apoptosis by inhibition of anti-apoptotic genes, and upregulation of apoptotic genes. Our results shed a light on aminopyrazoloandrostane deriv. 4 as an inhibitor of the PI3K/AKT/mTOR pathway, which might be acting as promising anti-liver cancer agent. Our data support further investigation of agents targeting the PI3K/AKT/mTOR.
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    Zhou, S.; Li, Y.; Gao, J.; Wang, Y.; Ma, X.; Ding, H.; Li, X.; Sun, S. Novel Protein Kinase C Phosphorylated Kinase Inhibitor-Matrine Suppresses Replication of Hepatitis B Virus via Modulating the Mitogen-Activated Protein Kinase Signal. https://doi.org/10.1080/21655979.2021.2024957 2022, 13 (2), 2851– 2865,  DOI: 10.1080/21655979.2021.2024957
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    Bender, D.; Hildt, E. Effect of Hepatitis Viruses on the Nrf2/Keap1-Signaling Pathway and Its Impact on Viral Replication and Pathogenesis. Int. J. Mol. Sci. 2019, Vol. 20, Page 4659 2019, 20 (18), 4659,  DOI: 10.3390/ijms20184659
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    Parker, P. J.; Brown, S. J.; Calleja, V.; Chakravarty, P.; Cobbaut, M.; Linch, M.; Marshall, J. J. T.; Martini, S.; McDonald, N. Q.; Soliman, T.; Watson, L. Equivocal, Explicit and Emergent Actions of PKC Isoforms in Cancer. Nat. Rev. Cancer 2020 211 2021, 21 (1), 51– 63,  DOI: 10.1038/s41568-020-00310-4
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    Yang, S.; Liu, Y.; Feng, X.; Wang, X.; Wu, M.; Gong, L.; Shu, B.; lu, Q.; Dong, J. HBx Acts as an Oncogene and Promotes the Invasion and Metastasis of Hepatocellular Carcinoma Both in Vivo and Vitro. Dig. Liver Dis. 2021, 53 (3), 360– 366,  DOI: 10.1016/j.dld.2020.10.007
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    25
    HBx acts as an oncogene and promotes the invasion and metastasis of hepatocellular carcinoma both in vivo and vitro
    Yang, Shizhong; Liu, Yanfeng; Feng, Xiaobin; Wang, Xiaojuan; Wu, Meilong; Gong, Lei; Shu, Bin; Qian, lu; Dong, Jiahong
    Digestive and Liver Disease (2021), 53 (3), 360-366CODEN: DLDIFK; ISSN:1590-8658. (Elsevier B.V.)
    Hepatitis B virus X (HBx) has been reported to be closely related to hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). This study aimed to detect the expression pattern of HBx and explore whether HBx protein can promote HCC invasion and metastasis both in vivo and vitro.HBx expression was detected in HCC tissues via immunochem. A recombinant adenovirus vector contg. the HBx gene was constructed and transfected into the HCC cell line SMMC-7721. Wound healing, transwell migration, and invasion assays were performed to evaluate migration and invasion potentials. A splenic implant tumor nude mice model was established to confirm its invasion and metastatic abilities in vivo.The pos. rate of HBx in HCC tissues was 67.89%. HBx overexpression significantly promoted the migration and invasion abilities of SMMC-7721 cells in vitro. The tumor model showed that splenic implant tumor vol. and no. of liver metastatic tumor nodes were significantly larger and higher in the HBx overexpression group than in the control group.HBx is highly expressed in HCC tissues and promotes HCC invasion and metastasis both in vivo and vitro with oncogene activity, thereby suggesting that HBx can serve as a novel therapeutic target in HCC.
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    Zhu, H.; Wang, Y.; Chen, J.; Cheng, G.; Xue, J. Transgenic Mice Expressing Hepatitis B Virus X Protein Are More Susceptible to Carcinogen Induced Hepatocarcinogenesis. Exp. Mol. Pathol. 2004, 76 (1), 44– 50,  DOI: 10.1016/j.yexmp.2003.09.001
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    26
    Transgenic mice expressing hepatitis B virus X protein are more susceptible to carcinogen induced hepatocarcinogenesis
    Zhu, Huanzhang; Wang, Yun; Chen, Jianquan; Cheng, Guoxiang; Xue, Jinglun
    Experimental and Molecular Pathology (2004), 76 (1), 44-50CODEN: EXMPA6; ISSN:0014-4800. (Elsevier Science)
    The hepatitis B virus X (HBx) protein is thought to be implicated in the development of human hepatocellular carcinoma (HCC), but its exact function remains controversial. To investigate whether the expression of the HBx gene alone can induce HCC on an inbred C57BL/6 strain that displays a lower spontaneous rate of liver cancer, and to det. if HBx transgenic mice are more susceptible to the effects of hepatocarcinogens, C57-TgN (HBx) X transgenic mice were bred with normal C57BL/6 mice strain. The F1 mice (about 50% HBx pos. and 50% HBx neg.) were treated with a single dose of diethylnitrosamine (DEN) at 7 days of age, or were untreated. Mice were killed at appropriate time points and were analyzed for histol. change in the liver. The expression of HBx protein were examd. by using immunohistochem. staining. Glycogen storage foci were examd. by using periodic acid-Schiff (PAS) staining. In HBx transgenic mice untreated with DEN, HBx expression and glycogen storage foci were always obsd. in the liver after 8 wk, but not obvious histol. pathol. changes. Histol. examn. of liver tissue confirmed that DEN-treated HBx mice developed approx. twice as many focal lesions of basophilic hepatocytes as treated wild-type littermates. Hepatocellular adenomas and carcinomas were also more frequent in DEN-treated HBx-pos. than HBx-neg. mice. Taken together, our results suggest that HBx gene expression alone is not sufficient for carcinogenesis, but may act as a promoter for malignant transformation.
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    Bouchard, M. J.; Wang, L. H.; Schneider, R. J. Calcium Signaling by HBx Protein in Hepatitis B Virus DNA Replication. Science (80-.). 2001, 294 (5550), 2376– 2378,  DOI: 10.1126/science.294.5550.2376
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    Burchell, A. N.; Winer, R. L.; de Sanjosé, S.; Franco, E. L. Epidemiology and Transmission Dynamics of Genital HPV Infection. In Vaccine; Elsevier, 2006; Vol. 24, pp S52- S61.  DOI: 10.1016/J.VACCINE.2006.05.031 .
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    Scott-Wittenborn, N.; Fakhry, C. Epidemiology of HPV Related Malignancies. Semin. Radiat. Oncol. 2021, 31 (4), 286– 296,  DOI: 10.1016/j.semradonc.2021.04.001
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    Epidemiology of HPV Related Malignancies
    Scott-Wittenborn Nicholas; Fakhry Carole
    Seminars in radiation oncology (2021), 31 (4), 286-296 ISSN:.
    Human papillomavirus is the most common sexually transmitted infection in the world and had been linked to both anogenital and oropharyngeal cancers. It causes nearly 100% of cervical cancers and an increasing portion of oropharyngeal cancers. The geographical burden of cervical HPV infection and associated cancers is not uniform and is mainly found in low middle income countries in South America, Africa, and Asia. However, HPV-positive oropharyngeal cancer is rapidly becoming more prevalent in high middle income countries. With the development of vaccines which prevent HPV infection, the World Health Organization has designated the extirpation of HPV and its associated cancers a priority. Countries that have implemented adequate vaccine programs have shown a decrease in HPV prevalence. Understanding the epidemiology of HPV and its associated cancers is fundamental in improving vaccine programs and other health programs.
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    Dahlström, L. A.; Andersson, K.; Luostarinen, T.; Thoresen, S.; Ögmundsdottír, H.; Tryggvadottír, L.; Wiklund, F.; Skare, G. B.; Eklund, C.; Sjölin, K.; Jellum, E.; Koskela, P.; Wadell, G.; Lehtinen, M.; Dillner, J. Prospective Seroepidemiologic Study of Human Papillomavirus and Other Risk Factors in Cervical Cancer. Cancer Epidemiol. Biomarkers Prev. 2011, 20 (12), 2541– 2550,  DOI: 10.1158/1055-9965.EPI-11-0761
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    Bravo, I. G.; de Sanjosé, S.; Gottschling, M. The Clinical Importance of Understanding the Evolution of Papillomaviruses. Trends Microbiol. 2010, 18 (10), 432– 438,  DOI: 10.1016/j.tim.2010.07.008
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    The clinical importance of understanding the evolution of papillomaviruses
    Bravo, Ignacio G.; de Sanjose, Silvia; Gottschling, Marc
    Trends in Microbiology (2010), 18 (10), 432-438CODEN: TRMIEA; ISSN:0966-842X. (Elsevier Ltd.)
    A review. A significant fraction of human cancers is assocd. with infections by different papillomaviruses (PVs). In other vertebrates, the presence of specific PVs is also assocd. with different neoplasias. The popular view of PVs conceives them to be largely static and relies on generalized assumptions that have rarely been rigorously tested such as: virus-host codivergence, strict tissue tropism and host-specificity, their very low mutation rate and the absence of recombination. Here, we want to stress the need and the medical importance of understanding the evolutionary history and present-day dynamics of PVs. Understanding the way that PV genomes have evolved will clarify the link between a given genotype and the phenotypic and clin. outcome of the corresponding viral infection.
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    Berman, B.; Amini, S.; Maderal, A. Condyloma Acuminata. Treat. Ski. Dis. Compr. Ther. Strateg. 2018, 288– 290,  DOI: 10.1016/B978-0-7020-6912-3.00089-6
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    Rose, A. B. Introns as Gene Regulators: A Brick on the Accelerator. Front. Genet. 2019, 9 (FEB), 672,  DOI: 10.3389/fgene.2018.00672
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    Schiller, J. T.; Lowy, D. R. Understanding and Learning from the Success of Prophylactic Human Papillomavirus Vaccines. Nat. Rev. Microbiol. 2012, 10 (10), 681– 692,  DOI: 10.1038/nrmicro2872
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    Understanding and learning from the success of prophylactic human papillomavirus vaccines
    Schiller, John T.; Lowy, Douglas R.
    Nature Reviews Microbiology (2012), 10 (10), 681-692CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)
    A review. An estd. 5% of human cancers are caused by human papillomavirus (HPV) infections, and most of these cancers are of the cervix. Two prophylactic HPV vaccines that target the two most oncogenic virus types, HPV16 and HPV18, are now com. available. In controlled clin. trials, the vaccines proved to be effective at preventing incident anogenital infection and the assocd. neoplastic disease that is induced by these virus types. Here, we highlight the specific aspects of HPV biol. and vaccine compn. that are likely to contribute to the efficacy of these vaccines, and we discuss how these particular features might or might not be relevant for the development of effective vaccines against other sexually transmitted viruses such as HIV and herpes simplex virus (HSV).
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    Yan, X.; Yu, Z.; Zhang, P.; Battisti, A. J.; Holdaway, H. A.; Chipman, P. R.; Bajaj, C.; Bergoin, M.; Rossmann, M. G.; Baker, T. S. The Capsid Proteins of a Large, Icosahedral DsDNA Virus. J. Mol. Biol. 2009, 385 (4), 1287,  DOI: 10.1016/j.jmb.2008.11.002
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    The Capsid Proteins of a Large, Icosahedral dsDNA Virus
    Yan, Xiaodong; Yu, Zeyun; Zhang, Ping; Battisti, Anthony J.; Holdaway, Heather A.; Chipman, Paul R.; Bajaj, Chandrajit; Bergoin, Max; Rossmann, Michael G.; Baker, Timothy S.
    Journal of Molecular Biology (2009), 385 (4), 1287-1299CODEN: JMOBAK; ISSN:0022-2836. (Elsevier Ltd.)
    Chilo iridescent virus (CIV) is a large (∼ 1850 Å diam.) insect virus with an icosahedral, T = 147 capsid, a double-stranded DNA (dsDNA) genome, and an internal lipid membrane. The structure of CIV was detd. to 13 Å resoln. by means of cryoelectron microscopy (cryoEM) and three-dimensional image reconstruction. A homol. model of P50, the CIV major capsid protein (MCP), was built based on its amino acid sequence and the structure of the homologous Paramecium bursaria chlorella virus 1 Vp54 MCP. This model was fitted into the cryoEM d. for each of the 25 trimeric CIV capsomers per icosahedral asym. unit. A difference map, in which the fitted CIV MCP capsomers were subtracted from the CIV cryoEM reconstruction, showed that there are at least three different types of minor capsid proteins assocd. with the capsomers outside the lipid membrane. "Finger" proteins are situated at many, but not all, of the spaces between three adjacent capsomers within each trisymmetron, and "zip" proteins are situated between sets of three adjacent capsomers at the boundary between neighboring trisymmetrons and pentasymmetrons. Based on the results of segmentation and d. correlations, there are at least eight finger proteins and three dimeric and two monomeric zip proteins in one asym. unit of the CIV capsid. These minor proteins appear to stabilize the virus by acting as intercapsomer crosslinks. One transmembrane "anchor" protein per icosahedral asym. unit, which extends from beneath one of the capsomers in the pentasymmetron to the internal leaflet of the lipid membrane, may provide addnl. stabilization for the capsid. These results are consistent with the observations for other large, icosahedral dsDNA viruses that also utilize minor capsid proteins for stabilization and for detg. their assembly.
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    Sapp, M.; Bienkowska-Haba, M. Viral Entry Mechanisms: Human Papillomavirus and a Long Journey from Extracellular Matrix to the Nucleus. FEBS J. 2009, 276 (24), 7206– 7216,  DOI: 10.1111/j.1742-4658.2009.07400.x
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    Viral entry mechanisms: human papillomavirus and a long journey from extracellular matrix to the nucleus
    Sapp, Martin; Bienkowska-Haba, Malgorzata
    FEBS Journal (2009), 276 (24), 7206-7216CODEN: FJEOAC; ISSN:1742-464X. (Wiley-Blackwell)
    A review. Papillomaviruses are epitheliotropic non-enveloped double-stranded DNA viruses, whose replication is strictly dependent on the terminally differentiating tissue of the epidermis. They induce self-limiting benign tumors of skin and mucosa, which may progress to malignancy (e.g. cervical carcinoma). Prior to entry into basal cells, virions attach to heparan sulfate moieties of the basement membrane. This triggers conformational changes, which affect both capsid proteins, L1 and L2, and such changes are a prerequisite for interaction with the elusive uptake receptor. These processes are very slow, resulting in an uptake half-time of up to 14 h. This minireview summarizes recent advances in our understanding of cell surface events, internalization and the subsequent intracellular trafficking of papillomaviruses.
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    Rubio, I.; Seitz, H.; Canali, E.; Sehr, P.; Bolchi, A.; Tommasino, M.; Ottonello, S.; Müller, M. The N-Terminal Region of the Human Papillomavirus L2 Protein Contains Overlapping Binding Sites for Neutralizing, Cross-Neutralizing and Non-Neutralizing Antibodies. Virology 2011, 409 (2), 348– 359,  DOI: 10.1016/j.virol.2010.10.017
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    The N-terminal region of the human papillomavirus L2 protein contains overlapping binding sites for neutralizing, cross-neutralizing and non-neutralizing antibodies
    Rubio, Ivonne; Seitz, Hanna; Canali, Elena; Sehr, Peter; Bolchi, Angelo; Tommasino, Massimo; Ottonello, Simone; Mueller, Martin
    Virology (2011), 409 (2), 348-359CODEN: VIRLAX; ISSN:0042-6822. (Elsevier B.V.)
    The N-terminal region of the human papillomavirus (HPV) L2 protein has been shown to contain immune epitopes able to induce the prodn. of neutralizing and cross-neutralizing antibodies. Using bacterial thioredoxin as a scaffold, we managed to enhance the immunogenicity of putative L2 neutralizing epitopes, but only a minor fraction of the resulting immune responses was found to be neutralizing. To det. the recognition patterns for non-neutralizing, neutralizing and cross-neutralizing antibodies, we isolated and characterized a panel of 46 monoclonal antibodies directed against different HPV16 L2 epitopes. Four of such antibodies proved to be neutralizing, and two of them, both targeting the amino acid (aa) 20-38 region of L2, were found to cross-neutralize a broad range of papillomaviruses. The epitopes recognized by neutralizing and cross-neutralizing antibodies were mapped at high resoln. and were found to be characterized by distinct recognition patterns. Even in the case of the L2 20-38 epitope, cross-neutralization of HPV31 pseudovirions proved to be extremely inefficient, and this was found to be primarily due to the lack of a proline residue at position 30. HPV16 specific amino acids in this region also appear to be responsible for the lack of cross-neutralizing activity, thus suggesting a potential immune escape mechanism. For the aa 71-80 region, instead, the data indicate that restriction of neutralization to HPV16 is due to sequence (or structural) differences laying outside of the epitope. Besides providing new insights on the mol. bases of L2-mediated immune reactivity, the present data may pave the way to novel vaccination approaches specifically evoking cross-neutralizing antibody responses.
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    Kines, R. C.; Thompson, C. D.; Lowy, D. R.; Schiller, J. T.; Day, P. M. The Initial Steps Leading to Papillomavirus Infection Occur on the Basement Membrane Prior to Cell Surface Binding. Proc. Natl. Acad. Sci. U. S. A. 2009, 106 (48), 20458– 20463,  DOI: 10.1073/pnas.0908502106
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    The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding
    Kines, Rhonda C.; Thompson, Cynthia D.; Lowy, Douglas R.; Schiller, John T.; Day, Patricia M.
    Proceedings of the National Academy of Sciences of the United States of America (2009), 106 (48), 20458-20463, S20458/1-S20458/5CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Using a murine challenge model, we previously detd. that human papillomavirus (HPV) pseudovirions initially bind preferentially to the cervicovaginal basement membrane (BM) at sites of trauma. We now report that the capsids undergo a conformational change while bound to the BM that results in L2 cleavage by a proprotein convertase (PC), furin, and/or PC5/6, followed by the exposure of an N-terminal cross-neutralization L2 epitope and transfer of the capsids to the epithelial cell surface. Prevention of this exposure by PC inhibition results in detachment of the pseudovirions from the BM and their eventual loss from the tissue, thereby preventing infection. Pseudovirions whose L2 had been precleaved by furin can bypass the PC inhibition of binding and infectivity. Cleavage of heparan sulfate proteoglycans (HSPG) with heparinase III prevented infection and BM binding by the precleaved pseudovirions, but did not prevent them from binding robustly to cell surfaces. These results indicate that the infectious process has evolved so that the initial steps take place on the BM, in contrast to the typical viral infection that is initiated by binding to the cell surface. The data are consistent with a dynamic model of in vivo HPV infection in which a conformational change and PC cleavage on the BM allows transfer of virions from HSPG attachment factors to an LI-specific receptor on basal keratinocytes migrating into the site of trauma.
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    Wang, J. W.; Roden, R. B. S. L2, the Minor Capsid Protein of Papillomavirus. Virology 2013, 445 (1–2), 175– 186,  DOI: 10.1016/j.virol.2013.04.017
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    L2, the minor capsid protein of papillomavirus
    Wang, Joshua W.; Roden, Richard B. S.
    Virology (2013), 445 (1-2), 175-186CODEN: VIRLAX; ISSN:0042-6822. (Elsevier B.V.)
    A review. The capsid protein L2 plays major roles in both papillomavirus assembly and the infectious process. While L1 forms the majority of the capsid and can self-assemble into empty virus-like particles (VLPs), L2 is a minor capsid component and lacks the capacity to form VLPs. However, L2 co-assembles with L1 into VLPs, enhancing their assembly. L2 also facilitates encapsidation of the ∼8 kbp circular and nucleosome-bound viral genome during assembly of the non-enveloped T=7d virions in the nucleus of terminally differentiated epithelial cells, although, like L1, L2 is not detectably expressed in infected basal cells. With respect to infection, L2 is not required for particles to bind to and enter cells. However L2 must be cleaved by furin for endosome escape. L2 then travels with the viral genome to the nucleus, wherein it accumulates at ND-10 domains. Here, we provide an overview of the biol. of L2.
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    Münger, K.; Baldwin, A.; Edwards, K. M.; Hayakawa, H.; Nguyen, C. L.; Owens, M.; Grace, M.; Huh, K. Mechanisms of Human Papillomavirus-Induced Oncogenesis. J. Virol. 2004, 78 (21), 11451,  DOI: 10.1128/JVI.78.21.11451-11460.2004
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    Mechanisms of human papillomavirus-induced oncogenesis
    Muenger, Karl; Baldwin, Amy; Edwards, Kirsten M.; Hayakawa, Hiroyuki; Nguyen, Christine L.; Owens, Michael; Grace, Miranda; Huh, KyungWon
    Journal of Virology (2004), 78 (21), 11451-11460CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
    A review. The role of E6 and E7 as oncoproteins of HPV in human oncogenesis is discussed.
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    Middleton, K.; Peh, W.; Southern, S.; Griffin, H.; Sotlar, K.; Nakahara, T.; El-Sherif, A.; Morris, L.; Seth, R.; Hibma, M.; Jenkins, D.; Lambert, P.; Coleman, N.; Doorbar, J. Organization of Human Papillomavirus Productive Cycle during Neoplastic Progression Provides a Basis for Selection of Diagnostic Markers. J. Virol. 2003, 77 (19), 10186– 10201,  DOI: 10.1128/JVI.77.19.10186-10201.2003
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    Organization of human papillomavirus productive cycle during neoplastic progression provides a basis for selection of diagnostic markers
    Middleton, Kate; Peh, Woei; Southern, Shirley; Griffin, Heather; Sotlar, Karl; Nakahara, Tomomi; El-Sherif, Amira; Morris, Lesley; Seth, Rashmi; Hibma, Merilyn; Jenkins, David; Lambert, Paul; Coleman, Nicholas; Doorbar, John
    Journal of Virology (2003), 77 (19), 10186-10201CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
    The productive cycle of human papillomaviruses (HPVs) can be divided into discrete phases. Cell proliferation and episomal maintenance in the lower epithelial layers are followed by genome amplification and the expression of capsid proteins. These events, which occur in all productive infections, can be distinguished by using antibodies to viral gene products or to surrogate markers of their expression. Here we have compared precancerous lesions caused by HPV type 16 (HPV16) with lesions caused by HPV types that are not generally assocd. with human cancer. These include HPV2 and HPV11, which are related to HPV16 (supergroup A), as well as HPV1 and HPV65, which are evolutionarily divergent (supergroups E and B). HPV16-induced low-grade squamous intraepithelial lesions (CIN1) are productive infections which resemble those caused by other HPV types. During progression to cancer, however, the activation of late events is delayed, and the thickness of the proliferative compartment is progressively increased. In many HPV16-induced high-grade squamous intraepithelial lesions (CIN3), late events are restricted to small areas close to the epithelial surface. Such heterogeneity in the organization of the productive cycle was seen only in lesions caused by HPV16 and was not apparent when lesions caused by other HPV types were compared. By contrast, the order in which events in the productive cycle were initiated was invariant and did not depend on the infecting HPV type or the severity of disease. The distribution of viral gene products in the infected cervix depends on the extent to which the virus can complete its productive cycle, which in turn reflects the severity of cervical neoplasia. It appears from our work that the presence of such proteins in cells at the epithelial surface allows the severity of the underlying disease to be predicted and that markers of viral gene expression may improve cervical screening.
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    Isaacson Wechsler, E.; Wang, Q.; Roberts, I.; Pagliarulo, E.; Jackson, D.; Untersperger, C.; Coleman, N.; Griffin, H.; Doorbar, J. Reconstruction of Human Papillomavirus Type 16-Mediated Early-Stage Neoplasia Implicates E6/E7 Deregulation and the Loss of Contact Inhibition in Neoplastic Progression. J. Virol. 2012, 86 (11), 6358– 6364,  DOI: 10.1128/JVI.07069-11
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    Reconstruction of human papillomavirus type 16-mediated early-stage neoplasia implicates E6/E7 deregulation and the loss of contact inhibition in neoplastic progression
    Isaacson Wechsler Erin; Wang Qian; Roberts Ian; Pagliarulo Emilio; Jackson Deborah; Untersperger Christina; Coleman Nick; Griffin Heather; Doorbar John
    Journal of virology (2012), 86 (11), 6358-64 ISSN:.
    Infection with human papillomavirus type 16 (HPV-16) can lead to low- or high-grade squamous intraepithelial lesions (LSIL or HSIL). Here we show that these in vivo disease states can be replicated in raft cultures of early-pass HPV-16 episomal cell lines, at both the level of pathology and the level of viral gene expression. A reduced responsiveness to cell-cell contact inhibition and an increase in E6/E7 activity correlated closely with phenotype. Similar deregulation is likely to underlie the appearance of LSIL or HSIL soon after infection.
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    Mittal, S.; Banks, L. Molecular Mechanisms Underlying Human Papillomavirus E6 and E7 Oncoprotein-Induced Cell Transformation. Mutat. Res. Rev. Mutat. Res. 2017, 772, 23– 35,  DOI: 10.1016/j.mrrev.2016.08.001
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    Molecular mechanisms underlying human papillomavirus E6 and E7 oncoprotein-induced cell transformation
    Mittal, Suruchi; Banks, Lawrence
    Mutation Research, Reviews in Mutation Research (2017), 772 (), 23-35CODEN: MRRRFK; ISSN:1383-5742. (Elsevier B.V.)
    Human papillomaviruses (HPVs) are the causative agents of 5% of all human cancers, with cervical cancer being the most important. Two viral oncoproteins, E6 and E7, are essential for the development and maintenance of malignancy. Both proteins function by targeting crit. pathways that are essential for maintaining cellular homeostasis. As a consequence of these activities, this produces an environment that is favorable for the normal viral life cycle, but when perturbed, can result in the initiation of changes to the host cell, which ultimately results in the development of a malignancy. In this review we discuss the role of these different functions of the viral oncoproteins during the viral life cycle and carcinogenesis, with an emphasis on how induction of DNA damage by the viral oncoproteins, in conjunction with the stem like nature of the target cells, can ultimately result in the development of cancer.
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    Doorbar, J.; Egawa, N.; Griffin, H.; Kranjec, C.; Murakami, I. Human Papillomavirus Molecular Biology and Disease Association. Rev. Med. Virol. 2015, 25 (S1), 2– 23,  DOI: 10.1002/rmv.1822
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    Human papillomavirus molecular biology and disease association
    Doorbar, John; Egawa, Nagayasu; Griffin, Heather; Kranjec, Christian; Murakami, Isao
    Reviews in Medical Virology (2015), 25 (S1), 2-23CODEN: RMVIEW; ISSN:1052-9276. (John Wiley & Sons Ltd.)
    Summary : Human papillomaviruses (HPVs) have evolved over millions of years to propagate themselves in a range of different animal species including humans. Viruses that have co-evolved slowly in this way typically cause chronic inapparent infections, with virion prodn. in the absence of apparent disease. This is the case for many Beta and Gamma HPV types. The Alpha papillomavirus types have however evolved immunoevasion strategies that allow them to cause persistent visible papillomas. These viruses activate the cell cycle as the infected epithelial cell differentiates in order to create a replication competent environment that allows viral genome amplification and packaging into infectious particles. This is mediated by the viral E6, E7, and E5 proteins. High-risk E6 and E7 proteins differ from their low-risk counterparts however in being able to drive cell cycle entry in the upper epithelial layers and also to stimulate cell proliferation in the basal and parabasal layers. Deregulated expression of these cell cycle regulators underlies neoplasia and the eventual progression to cancer in individuals who cannot resolve high-risk HPV infection. Most work to date has focused on the study of high-risk HPV types such as HPV 16 and 18, which has led to an understanding of the mol. pathways subverted by these viruses. Such approaches will lead to the development of better strategies for disease treatment, including targeted antivirals and immunotherapeutics. Priorities are now focused toward understanding HPV neoplasias at sites other than the cervix (e.g. tonsils, other transformation zones) and toward understanding the mechanisms by which low-risk HPV types can sometimes give rise to papillomatosis and under certain situations even cancers. Copyright © 2015 John Wiley & Sons, Ltd.
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    Galloway, D. A.; Laimins, L. A. Human Papillomaviruses: Shared and Distinct Pathways for Pathogenesis. Curr. Opin. Virol. 2015, 14, 87– 92,  DOI: 10.1016/j.coviro.2015.09.001
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    Human papillomaviruses: shared and distinct pathways for pathogenesis
    Galloway, Denise A.; Laimins, Laimonis A.
    Current Opinion in Virology (2015), 14 (), 87-92CODEN: COVUAF; ISSN:1879-6257. (Elsevier B. V.)
    A review. Over 200 types of human papillomaviruses (HPV) have been identified that infect epithelial cells at different anat. locations. HPVs are grouped into five genera with the alpha and beta viruses being the most commonly studied. Members of the alpha HPV genus infect genital epithelia and are the causative agents of many anogenital cancers. Beta HPVs infect cutaneous epithelia and have been suggested as co-factors in the development of non-melanoma skin cancers. Recent studies have shown that activation of DNA damage pathways is important for the productive life cycle of the alpha HPVs while the beta viruses suppress their activation. These differences likely contribute to the varying types of lesions and malignancies that are assocd. with these viruses.
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    Albrecht, D.; Meyer, T.; Lorenzen, T.; Stoehr, A.; Arndt, R.; Plettenberg, A. Epidemiology of HHV-8 Infection in HIV-Positive Patients with and without Kaposi Sarcoma: Diagnostic Relevance of Serology and PCR. J. Clin. Virol. 2004, 30 (2), 145– 149,  DOI: 10.1016/j.jcv.2003.09.017
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    Epidemiology of HHV-8 infection in HIV-positive patients with and without Kaposi sarcoma: diagnostic relevance of serology and PCR
    Albrecht Dirk; Meyer Thomas; Lorenzen Thore; Stoehr Albrecht; Arndt Ruediger; Plettenberg Andreas
    Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology (2004), 30 (2), 145-9 ISSN:1386-6532.
    BACKGROUND: Kaposi's sarcoma (KS) remains the most common neoplasm in HIV-infected patients. Human herpesvirus 8 (HHV-8) infection is etiologically associated with KS. Diagnostic procedures with regard to HHV-8 infection are not routinely performed in HIV-infected patients; diagnostic and prognostic value of HHV-8 serology or PCR are unknown in this setting. Epidemiological data concerning HHV-8 infection of HIV-infected patients in Germany are rare. OBJECTIVES: To assess prevalence of HHV-8 infection in a cohort of HIV-infected patients with and without KS in Germany and to correlate this to manifestations and clinical course of KS. STUDY DESIGN: HHV-8 serology was performed in 483 patients in routine care for HIV-infection in northern Germany. HHV-8 DNA was analyzed by PCR in peripheral blood mononuclear cells (PBMC) of 293 patients; in a subgroup multiple samples were analyzed. History and manifestations of KS were recorded. RESULTS: HHV-8 antibodies were detected using IFT in 91% of 33 patients with KS and 52% of 398 patients without KS. In 36 of 293 (12.3%) patients HHV-8 DNA was detected in PBMC. In general, HHV-8 DNA was not continuously detected when multiple samples from the same patient were analyzed. Patients with KS history were more likely to be PCR positive than those without (45.5% versus 7.8%). In patients with active KS HHV-8 DNA was detected more frequently than in patients with disease remission. HHV-8 DNA was not detected in serologically negative patients. However, three patients with KS history in full remission for several years were seronegative. CONCLUSIONS: HIV-infected patients were frequently found to be positive for HHV-8 antibodies. The number of patients positive for viral DNA in PBMC was much smaller. Single PCR-examinations were of little value for prognosis, but repeated detection of HHV-8 DNA represents an increased risk of disease activity.
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    Rohner, E.; Wyss, N.; Trelle, S.; Mbulaiteye, S. M.; Egger, M.; Novak, U.; Zwahlen, M.; Bohlius, J. HHV-8 Seroprevalence: A Global View. Syst. Rev. 2014, 3 (1), 1– 7,  DOI: 10.1186/2046-4053-3-11
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    Rewane, A; Tadi, P. Herpes virus type 8. In: StatPearls. StatPearls Publishing: Treasure Island (FL); 2022. pp. 1– 8. https://www.ncbi.nlm.nih.gov/books/NBK556023/.
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    Dittmer, D. P.; Damania, B. Kaposi Sarcoma-Associated Herpesvirus: Immunobiology, Oncogenesis, and Therapy. J. Clin. Invest. 2016, 126 (9), 3165– 3175,  DOI: 10.1172/JCI84418
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    Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy
    Dittmer Dirk P; Damania Blossom
    The Journal of clinical investigation (2016), 126 (9), 3165-75 ISSN:.
    Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, is the etiologic agent underlying Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. This human gammaherpesvirus was discovered in 1994 by Drs. Yuan Chang and Patrick Moore. Today, there are over five thousand publications on KSHV and its associated malignancies. In this article, we review recent and ongoing developments in the KSHV field, including molecular mechanisms of KSHV pathogenesis, clinical aspects of KSHV-associated diseases, and current treatments for cancers associated with this virus.
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    Purushothaman, P.; Uppal, T.; Verma, S. C. Molecular Biology of KSHV Lytic Reactivation. Viruses 2015, 7 (1), 116,  DOI: 10.3390/v7010116
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    Molecular biology of KSHV lytic reactivation
    Purushothaman, Pravinkumar; Uppal, Timsy; Verma, Subhash C.
    Viruses (2015), 7 (1), 116-153/1-116-153/38, 38 pp.CODEN: VIRUBR; ISSN:1999-4915. (MDPI AG)
    A review. Kaposi's sarcoma-assocd. herpesvirus (KSHV) primarily persists as a latent episome in infected cells. During latent infection, only a limited no. of viral genes are expressed that help to maintain the viral episome and prevent lytic reactivation. The latent KSHV genome persists as a highly ordered chromatin structure with bivalent chromatin marks at the promoter-regulatory region of the major immediate-early gene promoter. Various stimuli can induce chromatin modifications to an active euchromatic epigenetic mark, leading to the expression of genes required for the transition from the latent to the lytic phase of KSHV life cycle. Enhanced replication and transcription activator (RTA) gene expression triggers a cascade of events, resulting in the modulation of various cellular pathways to support viral DNA synthesis. RTA also binds to the origin of lytic DNA replication to recruit viral, as well as cellular, proteins for the initiation of the lytic DNA replication of KSHV. In this review we will discuss some of the pivotal genetic and epigenetic factors that control KSHV reactivation from the transcriptionally restricted latent program.
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    Cesarman, E.; Damania, B.; Krown, S. E.; Martin, J.; Bower, M.; Whitby, D. Kaposi Sarcoma. Nat. Rev. Dis. Prim. 2019 51 2019, 5 (1), 1– 21,  DOI: 10.1038/s41572-019-0060-9
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    Cousins, E.; Nicholas, J. Molecular Biology of Human Herpesvirus 8: Novel Functions and Virus-Host Interactions Implicated in Viral Pathogenesis and Replication. Recent Results Cancer Res. 2014, 193, 227,  DOI: 10.1007/978-3-642-38965-8_13
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    Molecular Biology of Human Herpesvirus 8: Novel Functions and Virus-Host Interactions Implicated in Viral Pathogenesis and Replication
    Cousins, Emily; Nicholas, John
    Recent Results in Cancer Research (2014), 193 (Viruses and Human Cancer), 227-268CODEN: RRCRBU; ISSN:2197-6767. (Springer GmbH)
    Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-assocd. herpesvirus (KSHV), is the second identified human gammaherpesvirus. Like its relative Epstein-Barr virus, HHV-8 is linked to B-cell tumors, specifically primary effusion lymphoma and multicentric Castleman's disease, in addn. to endothelial-derived KS. HHV-8 is unusual in its possession of a plethora of "accessory" genes and encoded proteins in addn. to the core, conserved herpesvirus and gammaherpesvirus genes that are necessary for basic biol. functions of these viruses. The HHV-8 accessory proteins specify not only activities deducible from their cellular protein homologies but also novel, unsuspected activities that have revealed new mechanisms of virus-host interaction that serve virus replication or latency and may contribute to the development and progression of virus-assocd. neoplasia. These proteins include viral interleukin-6 (vIL-6), viral chemokines (vCCLs), viral G protein-coupled receptor (vGPCR), viral interferon regulatory factors (vIRFs), and viral antiapoptotic proteins homologous to FLICE (FADD-like IL-1β converting enzyme)-inhibitory protein (FLIP) and survivin. Other HHV-8 proteins, such as signaling membrane receptors encoded by open reading frames K1 and K15, also interact with host mechanisms in unique ways and have been implicated in viral pathogenesis. Addnl., a set of micro-RNAs encoded by HHV-8 appear to modulate expression of multiple host proteins to provide conditions conducive to virus persistence within the host and could also contribute to HHV-8-induced neoplasia. Here, we review the mol. biol. underlying these novel virus-host interactions and their potential roles in both virus biol. and virus-assocd. disease.
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    Angius, F.; Ingianni, A.; Pompei, R. Human Herpesvirus 8 and Host-Cell Interaction: Long-Lasting Physiological Modifications, Inflammation and Related Chronic Diseases. Microorganisms 2020, 8 (3), 388,  DOI: 10.3390/microorganisms8030388
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    Human herpesvirus 8 and host-cell interaction: long-lasting physiological modifications, inflammation and related chronic diseases
    Angius, Fabrizio; Ingianni, Angela; Pompei, Raffaello
    Microorganisms (2020), 8 (3), 388CODEN: MICRKN; ISSN:2076-2607. (MDPI AG)
    Oncogenic and latent-persistent viruses belonging to both DNA and RNA groups are known to cause serious metab. alterations. Among these, the Human Herpesvirus 8 (HHV8) infection induces stable modifications in biochem. and cellular metab., which in turn affect its own pathol. properties. HHV8 enhances the expression of insulin receptors, supports the accumulation of neutral lipids in cytoplasmic lipid droplets and induces alterations in both triglycerides and cholesterol metab. in endothelial cells. In addn., HHV8 is also known to modify immune response and cytokine prodn. with implications for cell oxidative status (i.e., reactive oxygen species activation). This review underlines the recent findings regarding the role of latent and persistent HHV8 viral infection in host physiol. and pathogenesis.
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    Cannon, M.; Philpott, N. J.; Cesarman, E. The Kaposi’s Sarcoma-Associated Herpesvirus G Protein-Coupled Receptor Has Broad Signaling Effects in Primary Effusion Lymphoma Cells. J. Virol. 2003, 77 (1), 57,  DOI: 10.1128/JVI.77.1.57-67.2003
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    The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor has broad signaling effects in primary effusion lymphoma cells
    Cannon, Mark; Philpott, Nicola J.; Cesarman, Ethel
    Journal of Virology (2003), 77 (1), 57-67CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
    Kaposi's sarcoma-assocd. herpesvirus [KSHV/human herpesvirus 8 (HHV-8)] is a gamma-2-herpesvirus responsible for Kaposi's sarcoma as well as primary effusion lymphoma (PEL). KSHV is a lymphotropic virus that has pirated many mammalian genes involved in inflammation, cell cycle control, and angiogenesis. Among these is the early lytic viral G protein-coupled receptor (vGPCR), a homolog of the human interleukin-8 (IL-8) receptor. When expressed, vGPCR is constitutively active and can signal via mitogen- and stress-activated kinases. In certain models it activates the transcriptional potential of NF-κB and activator protein 1 (AP-1) and induces vascular endothelial growth factor (VEGF) prodn. Despite its importance to the pathogenesis of all KSHV-mediated disease, little is known about vGPCR activity in hematopoietic cells. To study the signaling potential and downstream effects of vGPCR in such cells, the authors have developed PEL cell lines that express vGPCR under the control of an inducible promoter. The sequences required for tetracycline-mediated induction were cloned into a plasmid contg. adeno-assocd. virus type 2 elements to enhance integration efficiency. This novel plasmid permitted studies of vGPCR activity in naturally infected KSHV-pos. lymphocytes. The authors show that vGPCR activates ERK-2 and p38 in PEL cells. In addn., it increases the transcription of reporter genes under the control of AP-1, NF-κB, CREB, and NFAT, a Ca2+-dependent transcription factor important to KSHV lytic gene expression. VGPCR also increases the transcription of KSHV open reading frames 50 and 57, thereby displaying broad potential to affect viral transcription patterns. Finally, vGPCR signaling results in increased PEL cell elaboration of KSHV vIL-6 and VEGF, growth factors involved in KSHV-mediated disease pathogenesis.
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    Brinkmann, M. M.; Pietrek, M.; Dittrich-Breiholz, O.; Kracht, M.; Schulz, T. F. Modulation of Host Gene Expression by the K15 Protein of Kaposi’s Sarcoma-Associated Herpesvirus. J. Virol. 2007, 81 (1), 42,  DOI: 10.1128/JVI.00648-06
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    Modulation of host gene expression by the K15 protein of Kaposi's sarcoma-associated herpesvirus
    Brinkmann, Melanie M.; Pietrek, Marcel; Dittrich-Breiholz, Oliver; Kracht, Michael; Schulz, Thomas F.
    Journal of Virology (2007), 81 (1), 42-58CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
    Kaposi's sarcoma-assocd. herpesvirus (KSHV) contains several open reading frames (ORFs) encoding proteins capable of initiating signal transduction pathways. Among them is the K15 ORF, which consists of eight exons encoding a protein with 12 predicted transmembrane domains and a cytoplasmic C terminus. When transiently expressed, the 8-exon K15 transcript gives rise to a protein with an apparent mol. mass of 45 kDa. K15 interacts with cellular proteins, TRAF (tumor necrosis factor receptor-assocd. factor) and Src kinases, and activates AP-1, NF-κB, and the mitogen-activated protein kinases (MAPKs) c-jun-N-terminal kinase and extracellular signal-regulated kinase. This signaling activity of K15 is related to phosphorylation of Y481 of the K15 SH2-B motif Y481 EEV. In this study we demonstrate the expression of an endogenous 45-kDa K15 protein in KSHV BAC36-infected epithelial cells. This endogenous K15 protein shows the same intracellular localization as transiently expressed K15, and expression kinetic studies suggest it to be a lytic gene. We have further detd. the downstream target genes of K15 signaling using DNA oligonucleotide microarrays. We demonstrate that K15 is capable of inducing expression of multiple cytokines and chemokines, including interleukin-8 (IL-8), IL-6, CCL20, CCL2, CXCL3, and IL-1α/β, as well as expression of Dscr1 and Cox-2. In epithelial cells, K15-induced upregulation of most genes was dependent on phosphorylation of Y481, whereas in endothelial cells mutation of Y481 did not result in a complete loss of Dscr1 and Cox-2 expression and NFAT-activity. Our study establishes K15 as one of the KSHV lytic genes that are inducing expression of multiple cytokines, which have been shown to play an important role in KSHV-assocd. pathogenesis.
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    Caselli, E.; Fiorentini, S.; Amici, C.; Di Luca, D.; Caruso, A.; Santoro, M. G. Human Herpesvirus 8 Acute Infection of Endothelial Cells Induces Monocyte Chemoattractant Protein 1-Dependent Capillary-like Structure Formation: Role of the IKK/NF-KappaB Pathway. Blood 2007, 109 (7), 2718– 2726,  DOI: 10.1182/blood-2006-03-012500
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    Human herpesvirus 8 acute infection of endothelial cells induces monocyte chemoattractant protein 1-dependent capillary-like structure formation: role of the IKK/NF-κB pathway
    Caselli, Elisabetta; Fiorentini, Simona; Amici, Carla; Di Luca, Dario; Caruso, Arnaldo; Santoro, M. Gabriella
    Blood (2007), 109 (7), 2718-2726CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)
    Human herpesvirus 8 (HHV-8) is considered the causative agent of Kaposi sarcoma, a highly vascularized neoplasm characterized by spindle-shaped cells of endothelial origin and inflammatory cell infiltration. The cell transforming ability of HHV-8 has been assocd. with the activation of NF-κB, a nuclear factor playing a pivotal role in promoting inflammation and cell proliferation; however, little is known about NF-κB activation during acute HHV-8 infection. In the present study, we used a recently established in vitro model of HHV-8 acute productive infection in endothelial cells to investigate the effect of HHV-8 on NF-κB activity and function. HHV-8 rapidly and potently induced NF-κB activity in endothelial cells via stimulation of the IκB kinase (IKK). Following IKK activation, HHV-8 selectively triggered the prodn. of high levels of monocyte chemoattractant protein 1 (MCP-1), whereas it did not affect the expression of other NF-κB-dependent proinflammatory proteins, including TNF-α, IL-8, and RANTES. Deletion of NF-κB-binding sites in the MCP-1 enhancer resulted in significant inhibition of HHV-8-induced transcription. Furthermore, MCP-1 prodn. was accompanied by virus-induced capillary-like structure formation at early stages of infection. The results suggest that HHV-8-induced MCP-1 may play an important role in promoting inflammation and pathogenic angiogenesis typical of HHV-8-assocd. lesions.
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    Jham, B. C.; Montaner, S. The Kaposi’s Sarcoma-Associated Herpesvirus G Protein Coupled Receptor: Lessons on Dysregulated Angiogenesis from a Viral Oncogene. J. Cell. Biochem. 2010, 110 (1), 1,  DOI: 10.1002/jcb.22524
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    The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor: lessons on dysregulated angiogenesis from a viral oncogene
    Jham, Bruno C.; Montaner, Silvia
    Journal of Cellular Biochemistry (2010), 110 (1), 1-9CODEN: JCEBD5; ISSN:0730-2312. (Wiley-Liss, Inc.)
    A review. Tumor viruses can induce cell transformation by overcoming cellular defense mechanisms and promoting the ungoverned proliferation of infected cells. To this end, functionally related viral oncogenes have evolved in disparate viruses to over-ride key proliferative and survival intracellular pathways, thus assuring efficient viral replication and contributing to tumor formation. Indeed, the study of viral oncogenes was a powerful tool for disclosing fundamental insights into these basic cellular processes. In this regard, the Kaposi's sarcoma-assocd. herpesvirus (KSHV or HHV8), the etiol. agent of Kaposi's sarcoma (KS), is an exemplary model of an oncogenic virus that includes within its genome several homologues of cellular genes implicated in the regulation of cell proliferation and apoptosis. However, emerging evidence now points to a single KSHV gene, ORF74, encoding for the viral G protein-coupled receptor (vGPCR), as essential for KS development. Expressed in only a fraction of cells within KS lesions, this viral receptor induces tumorigenesis through both autocrine and paracrine mechanisms. Indeed, work from several labs. has demonstrated that vGPCR can promote cell proliferation, enhance cell survival, modulate cell migration, stimulate angiogenesis, and recruit inflammatory cells, both in expressing cells, as well as in neighboring (bystander) cells. Examn. of this powerful viral oncogene may expose novel targets for the treatment of patients with KS and could ultimately provide a unique perspective into how GPCRs, and specifically chemokine receptors, contribute to angiogenesis and tumorigenesis.
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    Verma, S. C.; Lan, K.; Robertson, E. Structure and Function of Latency-Associated Nuclear Antigen. Curr. Top. Microbiol. Immunol. 2007, 312, 101,  DOI: 10.1007/978-3-540-34344-8_4
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    Structure and function of latency-associated nuclear antigen
    Verma, S. C.; Lan, K.; Robertson, E.
    Current Topics in Microbiology and Immunology (2007), 312 (Kaposi Sarcoma Herpesvirus), 101-136CODEN: CTMIA3; ISSN:0070-217X. (Springer GmbH)
    A review. Latency-assocd. nuclear antigen (LANA) encoded by open reading frame 73 (ORF73) is the major latent protein expressed in all forms of KSHV-assocd. malignancies. LANA is a large (222-234 kDa) nuclear protein that interacts with various cellular as well as viral proteins. LANA has been classified as an oncogenic protein as it dysregulates various cellular pathways including tumor suppressor pathways assocd. with pRb and p53 and can transform primary rat embryo fibroblasts in cooperation with the cellular oncogene Hras. It assocs. with GSK-3β, an important modulator of Wnt signaling pathway leading to the accumulation of cytoplasmic β-catenin, which upregulates Tcf/Lef regulated genes after entering into the nucleus. LANA also blocks the expression of RTA, the reactivation transcriptional activator, which is crit. for the latency to lytic switch, and thus helps in maintaining viral latency. LANA tethers the viral episomal DNA to the host chromosomes by directly binding to its cognate binding sequence within the TR region of the genome through its C terminus and to the nucleosomes through the N terminus of the mol. Tethering to the host chromosomes helps in efficient partitioning of the viral episomes in the dividing cells. Disruptions of LANA expression led to redn. in the episomal copies of the viral DNA, supporting its role in persistence of the viral DNA. The functions known so far suggest that LANA is a key player in KSHV-mediated pathogenesis.
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    Jarrett, A. F.; Armstrong, A. A.; Alexander, E. Epidemiology of EBV and Hodgkin’s Lymphoma. Ann. Oncol. 1996, 7 (SUPPL. 4), S5– S10,  DOI: 10.1093/annonc/7.suppl_4.S5
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    Epidemiology of EBV and Hodgkin's lymphoma
    Jarrett A F; Armstrong A A; Alexander E
    Annals of oncology : official journal of the European Society for Medical Oncology (1996), 7 Suppl 4 (), 5-10 ISSN:0923-7534.
    The incidence of Hodgkin's disease shows marked heterogeneity with respect to age, gender, race, geographical locale, social class and histological subtype. The Epstein-Barr virus (EBV) is associated with a proportion of cases, approximately 40% in developed countries, and there is a body of evidence which suggests that mixed cellularity Hodgkin's disease is more likely to be EBV-associated than nodular sclerosis Hodgkin's disease. This study investigates the relationship between EBV and both age and histological subtype. We confirm the above subtype distribution and that childhood and older adult cases are more likely to be EBV-associated than young adult cases. Young adult nodular sclerosis cases are rarely EBV-associated providing further evidence that this is a separate disease entity. The results of this study support the multiple aetiology hypothesis which suggests that Hodgkin's disease in different age groups has different aetiologies. The epidemiology of Hodgkin's disease and studies investigating the distribution of EBV-associated cases are reviewed.
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    Swerdlow, S. H.; Campo, E.; Pileri, S. A.; Harris, N. L.; Stein, H.; Siebert, R.; Advani, R.; Ghielmini, M.; Salles, G. A.; Zelenetz, A. D.; Jaffe, E. S. The 2016 Revision of the World Health Organization Classification of Lymphoid Neoplasms. Blood 2016, 127 (20), 2375– 2390,  DOI: 10.1182/blood-2016-01-643569
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    The 2016 revision of the World Health Organization classification of lymphoid neoplasms
    Swerdlow, Steven H.; Campo, Elias; Pileri, Stefano A.; Harris, Nancy Lee; Stein, Harald; Siebert, Reiner; Advani, Ranjana; Ghielmini, Michele; Salles, Gilles A.; Zelenetz, Andrew D.; Jaffe, Elaine S.
    Blood (2016), 127 (20), 2375-2390CODEN: BLOOAW; ISSN:1528-0020. (American Society of Hematology)
    A revision of the nearly 8-yr-old World Health Organization classification of the lymphoid neoplasms and the accompanying monograph is being published. It reflects a consensus among hematopathologists, geneticists, and clinicians regarding both updates to current entities as well as the addn. of a limited no. of new provisional entities. The revision clarifies the diagnosis and management of lesions at the very early stages of lymphomagenesis, refines the diagnostic criteria for some entities, details the expanding genetic/mol. landscape of numerous lymphoid neoplasms and their clin. correlates, and refers to investigations leading to more targeted therapeutic strategies. The major changes are reviewed with an emphasis on the most important advances in our understanding that impact our diagnostic approach, clin. expectations, and therapeutic strategies for the lymphoid neoplasms.
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    Hjalgrim, H.; Friborg, J.; Melbye, M. The Epidemiology of EBV and Its Association with Malignant Disease. Hum. Herpesviruses Biol. Ther. Immunoprophyl. 2007, 929– 959,  DOI: 10.1017/CBO9780511545313.054
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    Aalto, S. M.; Juvonen, E.; Tarkkanen, J.; Volin, L.; Haario, H.; Ruutu, T.; Hedman, K. Epstein-Barr Viral Load and Disease Prediction in a Large Cohort of Allogeneic Stem Cell Transplant Recipients. Clin. Infect. Dis. 2007, 45 (10), 1305– 1309,  DOI: 10.1086/522531
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    Epstein-Barr viral load and disease prediction in a large cohort of allogeneic stem cell transplant recipients
    Aalto S M; Juvonen E; Tarkkanen J; Volin L; Haario H; Ruutu T; Hedman K
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (2007), 45 (10), 1305-9 ISSN:.
    BACKGROUND: We wanted to determine the clinical significance and predictability of Epstein-Barr virus (EBV) infections among a large cohort of recipients of allogeneic, unselected stem cell transplants. METHODS: During 1988-1999, a total of 5479 consecutive serum samples obtained during 406 transplantations performed in Helsinki, Finland, were retrospectively analyzed by quantitative polymerase chain reaction for the presence of EBV DNA. RESULTS: Overall, EBV DNA was noted in at least 1 serum sample for 57 patients (14.0%), of whom 22 (5.4%) were found to have progressively increasing and ultimately high (>50,000 copies/mL) EBV DNA levels (median level, 179,000 copies/mL). In addition, 16 patients (4.0%) had low EBV DNA levels (median level, 3260 copies/mL) in isolated sera before death. Among the transplant recipients who survived, transient EBV DNAemia (median level, 3110 copies/mL), which apparently corresponded to asymptomatic EBV infection, was noted in 19 patients (4.7%). CONCLUSIONS: Low-level EBV DNA positivity in serum occurs relatively frequently after stem cell transplantation and may subside without specific treatment. However, high EBV DNA levels (i.e., >50,000 copies/mL) are strong predictors for the development of posttransplantation lymphoproliferative disease, are not spontaneously reversible, and should be treated immediately. If the EBV DNA level is >or=50,000 copies/mL, the patient can be classified as having life-threatening EBV infection.
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    Dunmire, S. K.; Grimm, J. M.; Schmeling, D. O.; Balfour, H. H.; Hogquist, K. A. The Incubation Period of Primary Epstein-Barr Virus Infection: Viral Dynamics and Immunologic Events. PLoS Pathog. 2015, 11 (12), e1005286,  DOI: 10.1371/journal.ppat.1005286
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    The incubation period of primary epstein-barr virus infection: viral dynamics and immunologic events
    Dunmire, Samantha K.; Grimm, Jennifer M.; Schmeling, David O.; Balfour, Henry H., Jr.; Hogquist, Kristin A.
    PLoS Pathogens (2015), 11 (12), e1005286/1-e1005286/18CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
    Epstein-Barr virus (EBV) is a human herpesvirus that causes acute infectious mononucleosis and is assocd. with cancer and autoimmune disease. While many studies have been performed examg. acute disease in adults following primary infection, little is known about the virol. and immunol. events during EBV's lengthy 6 wk incubation period owing to the challenge of collecting samples from this stage of infection. We conducted a prospective study in college students with special emphasis on frequent screening to capture blood and oral wash samples during the incubation period. Here we describe the viral dissemination and immune response in the 6 wk prior to onset of acute infectious mononucleosis symptoms. While virus is presumed to be present in the oral cavity from time of transmission, we did not detect viral genomes in the oral wash until one week before symptom onset, at which time viral genomes were present in high copy nos., suggesting loss of initial viral replication control. In contrast, using a sensitive nested PCR method, we detected viral genomes at low levels in blood about 3 wk before symptoms. However, high levels of EBV in the blood were only obsd. close to symptom onset-coincident with or just after increased viral detection in the oral cavity. These data imply that B cells are the major reservoir of virus in the oral cavity prior to infectious mononucleosis. The early presence of viral genomes in the blood, even at low levels, correlated with a striking decrease in the no. of circulating plasmacytoid dendritic cells well before symptom onset, which remained depressed throughout convalescence. On the other hand, natural killer cells expanded only after symptom onset. Likewise, CD4+ Foxp3+ regulatory T cells decreased two fold, but only after symptom onset. We obsd. no substantial virus specific CD8 T cell expansion during the incubation period, although polyclonal CD8 activation was detected in concert with viral genomes increasing in the blood and oral cavity, possibly due to a systemic type I interferon response. This study provides the first description of events during the incubation period of natural EBV infection in humans and definitive data upon which to formulate theories of viral control and disease pathogenesis.
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    Balfour, H. H.; Dunmire, S. K.; Hogquist, K. A. Infectious Mononucleosis. Clin. Transl. Immunol. 2015, 4 (2), e33  DOI: 10.1038/cti.2015.1
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    Infectious mononucleosis
    Balfour, Henry H., Jr.; Dunmire, Samantha K.; Hogquist, Kristin A.
    Clinical and Translational Immunology (2015), 4 (), e33CODEN: CTILBR; ISSN:2050-0068. (NPG Nature Asia-Pacific)
    Infectious mononucleosis is a clin. entity characterized by pharyngitis, cervical lymph node enlargement, fatigue and fever, which results most often from a primary Epstein-Barr virus (EBV) infection. EBV, a lymphocrytovirus and a member of the γ-herpesvirus family, infects at least 90% of the population worldwide, the majority of whom have no recognizable illness. The virus is spread by intimate oral contact among adolescents, but how preadolescents acquire the virus is not known. During the incubation period of approx. 6 wk, viral replication first occurs in the oropharynx followed by viremia as early as 2 wk before onset of illness. The acute illness is marked by high viral loads in both the oral cavity and blood accompanied by the prodn. of IgM antibodies against EBV viral capsid antigen and an extraordinary expansion of CD8+ T lymphocytes directed against EBV-infected B cells. During convalescence, CD8+ T cells return to normal levels and antibodies develop against EBV nuclear antigen-1. A typical clin. picture in an adolescent or young adult with a pos. heterophile test is usually sufficient to make the diagnosis of infectious mononucleosis, but heterophile antibodies are not specific and do not develop in some patients esp. young children. EBV-specific antibody profiles are the best choice for staging EBV infection. In addn. to causing acute illness, long-term consequences are linked to infectious mononucleosis, esp. Hodgkin lymphoma and multiple sclerosis. There is no licensed vaccine for prevention and no specific approved treatment. Future research goals are development of an EBV vaccine, understanding the risk factors for severity of the acute illness and likelihood of developing cancer or autoimmune diseases, and discovering anti-EBV drugs to treat infectious mononucleosis and other EBV-spurred diseases.
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  65. 65
    Pannone, G.; Zamparese, R.; Pace, M.; Pedicillo, M. C.; Cagiano, S.; Somma, P.; Errico, M. E.; Donofrio, V.; Franco, R.; De Chiara, A.; Aquino, G.; Bucci, P.; Bucci, E.; Santoro, A.; Bufo, P. The Role of EBV in the Pathogenesis of Burkitt’s Lymphoma: An Italian Hospital Based Survey. Infect. Agent. Cancer 2014, 9 (1), 34,  DOI: 10.1186/1750-9378-9-34
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    65
    The role of EBV in the pathogenesis of Burkitt's Lymphoma: an Italian hospital based survey
    Pannone, Giuseppe; Zamparese, Rosanna; Pace, Mirella; Pedicillo, Maria Carmela; Cagiano, Simona; Somma, Pasquale; Errico, Maria Elena; Donofrio, Vittoria; Franco, Renato; De Chiara, Annarosaria; Aquino, Gabriella; Bucci, Paolo; Bucci, Eduardo; Santoro, Angela; Bufo, Pantaleo
    Infectious Agents and Cancer (2014), 9 (), 34/1-34/11, 11 pp.CODEN: IACNB4; ISSN:1750-9378. (BioMed Central Ltd.)
    The exact worldwide incidence of Burkitt's lymphoma is not known. There are three distinct clin. variants of Burkitt's lymphoma, each manifesting differences in epidemiol., clin. presentation, morphol., biol. and genetic features: the endemic (African), the sporadic (non-endemic), and the immunodeficiency-assocd. form. In particular, we reported data regarding Burkitt's lymphoma incidence in the world and across different European countries. Finally, we described clinic-pathol. data of 48 Burkitt's lymphomas occurred in Italy from 2003 to 2013, in 4 different hospitals, two of which located in east side, and the other ones located in the west-coast. Forty Burkitt's lymphomas occurs in children (age range 3-12), and 8 were adulthood Burkitt's lymphomas (age range 18-87). In the pediatric group the Male:Female ratio (M:F) was of 4:1, whereas the group of the adult patients has a M:F of 1:1.67. Immunohistochem. detection of Latent Membrane Protein 1 (LMP1) expression and Epstein-Barr virus Encoded RNA (EBER) In Situ Hybridization (ISH) procedures have been performed. Lymphocyte B monoclonal spread has been demonstrated using a Polymerase Chain Reaction (PCR) based method to amplify Fragment Restriction FR1, FR2 and FR3 Ig heavy chains DNA fragments. Only 38 cases out of 48 were analyzed for LMP-1 showing various percentage of stained cells in 47.4% of the patients. Considering ISH for EBER detection results: - 1 out 2 (50%) adult analyzed cases was pos., with 50% of stained tumor cells (this patient was a 22 years old female, coming from Napoli); - 15 out 24 (62.5%) children analyzed Burkitt's lymphomas resulted as pos. for EBER; - the overall positivity has been obsd. in 16/26 Burkitt's lymphomas (61.53%). - Finally, EBV has been detected in children and adult patients, one of them with deregulation of the oncogene c-MYC by chromosomal translocation.
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  66. 66
    Pavlovic, A.; Glavina Durdov, M.; Capkun, V.; Jakelic Pitesa, J.; Bozic Sakic, M. Classical Hodgkin Lymphoma with Positive Epstein-Barr Virus Status Is Associated with More FOXP3 Regulatory T Cells. Med. Sci. Monit. 2016, 22, 2340,  DOI: 10.12659/MSM.896629
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    Classical Hodgkin lymphoma with positive epstein-barr virus status is associated with more FOXP3 regulatory T cells
    Pavlovic, Antonia; Durdov, Merica Glavina; Capkun, Vesna; Pitesa, Jasminka Jakelic; Sakic, Maja Bozic
    Medical Science Monitor (2016), 22 (), 2340-2346CODEN: MSMOFR; ISSN:1643-3750. (International Scientific Information, Inc.)
    Background: Classical Hodgkin lymphoma (cHL) is characterized by sparse malignant Hodgkin and Reed-Sternberg cells dispersed in an inflammatory microenvironment. Immune evasion of malignant cells is partially due to the existence of a subpopulation of immunosuppressive regulatory T cells (Treg). The aim of this study was to analyze T cell compn. in cHL with special emphasis on Treg in regard to Epstein-Barr virus (EBV) status, subtype, and patient age. Material/Methods: The study included 102 patients with cHL diagnosed during a 12-yr period. EBV status of cHL was assessed immunohistochem. using antibodies directed to the EBV- encoded LMP1. To define T lymphocyte populations, slides were double-stained with FOXP3 for Treg, and CD4 or CD8 for T cells. In each case the no. of single- and/or double-pos. cells was counted on an image analyzer in 10 high-power fields. Statistical anal. was performed and differences were considered significant at P<0.05. Results: EBV-pos. status of cHL was confirmed in 30 (29%) cases, mainly in patients older than 54 years and in mixed cellularity subtype. In EBV-pos. cHL, higher nos. of CD8+ cells were found. In cHL with pos. EBV status, more FOXP3+ Treg were found, as well as higher nos. of FOXP3+CD4+ Treg compared with EBV-neg. cHL. The no. of CD4+ cells decreased with age. The frequency of FOXP3+CD8+ Treg was variable, without a statistically significant assocn. with age or EBV status. Conclusions: EBV status has an impact on compn. of T cell populations in the cHL microenvironment.
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  67. 67
    Carbone, A.; Gloghini, A.; Dotti, G. EBV-Associated Lymphoproliferative Disorders: Classification and Treatment. Oncologist 2008, 13 (5), 577– 585,  DOI: 10.1634/theoncologist.2008-0036
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    EBV-associated lymphoproliferative disorders: classification and treatment
    Carbone Antonino; Gloghini Annunziata; Dotti Giampietro
    The oncologist (2008), 13 (5), 577-85 ISSN:1083-7159.
    Since its discovery as the first human tumor virus, Epstein-Barr virus (EBV) has been implicated in the development of a wide range of B-cell lymphoproliferative disorders, including Burkitt's lymphoma, classic Hodgkin's lymphoma, and lymphomas arising in immunocompromised individuals (post-transplant and HIV-associated lymphoproliferative disorders). T-cell lymphoproliferative disorders that have been reported to be EBV associated include a subset of peripheral T-cell lymphomas, angioimmunoblastic T-cell lymphoma, extranodal nasal type natural killer/T-cell lymphoma, and other rare histotypes. EBV encodes a series of products interacting with or exhibiting homology to a wide variety of antiapoptotic molecules, cytokines, and signal transducers, hence promoting EBV infection, immortalization, and transformation. However, the exact mechanism by which EBV promotes oncogenesis is an area of active debate. The focus of this review is on the pathology, diagnosis, classification, and pathogenesis of EBV-associated lymphomas. Recent advances in EBV cell-based immunotherapy, which is beginning to show promise in the treatment of EBV-related disorders, are discussed.
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    Cai, Q.; Chen, K.; Young, K. H. Epstein-Barr Virus-Positive T/NK-Cell Lymphoproliferative Disorders. Exp. Mol. Med. 2015, 47 (1), e133,  DOI: 10.1038/emm.2014.105
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    Epstein-Barr virus-positive T/NK-cell lymphoproliferative disorders
    Cai, Qingqing; Chen, Kailin; Young, Ken H.
    Experimental & Molecular Medicine (2015), 47 (1), e133CODEN: EMMEF3; ISSN:2092-6413. (NPG Nature Asia-Pacific)
    A review. Epstein-Barr virus, a ubiquitous human herpesvirus, can induce both lytic and latent infections that result in a variety of human diseases, including lymphoproliferative disorders. The oncogenic potential of Epstein-Barr virus is related to its ability to infect and transform B lymphocytes into continuously proliferating lymphoblastoid cells. However, Epstein-Barr virus has also been implicated in the development of T/natural killer cell lymphoproliferative diseases. Epstein-Barr virus encodes a series of products that mimic several growth, transcription and anti-apoptotic factors, thus usurping control of pathways that regulate diverse homeostatic cellular functions and the microenvironment. However, the exact mechanism by which Epstein-Barr virus promotes oncogenesis and inflammatory lesion development remains unclear. Epstein-Barr virus-assocd. T/natural killer cell lymphoproliferative diseases often have overlapping clin. symptoms as well as histol. and immunophenotypic features because both lymphoid cell types derive from a common precursor. Accurate classification of Epstein-Barr virus-assocd. T/natural killer cell lymphoproliferative diseases is a prerequisite for appropriate clin. management. Currently, the treatment of most T/natural killer cell lymphoproliferative diseases is less than satisfactory. Novel and targeted therapies are strongly required to satisfy clin. demands. This review describes our current knowledge of the genetics, oncogenesis, biol., diagnosis and treatment of Epstein-Barr virus-assocd. T/natural killer cell lymphoproliferative diseases.
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    Jácome, A. A. dos A.; de Lima, E. M.; Kazzi, A. I.; Chaves, G. F.; de Mendonça, D. C.; Maciel, M. M.; dos Santos, J. S. Epstein-Barr Virus-Positive Gastric Cancer: A Distinct Molecular Subtype of the Disease?. Rev. Soc. Bras. Med. Trop. 2016, 49 (2), 150– 157,  DOI: 10.1590/0037-8682-0270-2015
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    69
    Epstein-Barr virus-positive gastric cancer: a distinct molecular subtype of the disease?
    Jacome Alexandre Andrade Dos Anjos; Lima Enaldo Melo de; Kazzi Ana Izabela; Chaves Gabriela Freitas; Mendonca Diego Cavalheiro de; Maciel Marina Mara; Santos Jose Sebastiao Dos
    Revista da Sociedade Brasileira de Medicina Tropical (2016), 49 (2), 150-7 ISSN:.
    Approximately 90% of the world population is infected by Epstein-Barr virus (EBV). Usually, it infects B lymphocytes, predisposing them to malignant transformation. Infection of epithelial cells occurs rarely, and it is estimated that about to 10% of gastric cancer patients harbor EBV in their malignant cells. Given that gastric cancer is the third leading cause of cancer-related mortality worldwide, with a global annual incidence of over 950,000 cases, EBV-positive gastric cancer is the largest group of EBV-associated malignancies. Based on gene expression profile studies, gastric cancer was recently categorized into four subtypes; EBV-positive, microsatellite unstable, genomically stable and chromosomal instability. Together with previous studies, this report provided a more detailed molecular characterization of gastric cancer, demonstrating that EBV-positive gastric cancer is a distinct molecular subtype of the disease, with unique genetic and epigenetic abnormalities, reflected in a specific phenotype. The recognition of characteristic molecular alterations in gastric cancer allows the identification of molecular pathways involved in cell proliferation and survival, with the potential to identify therapeutic targets. These findings highlight the enormous heterogeneity of gastric cancer, and the complex interplay between genetic and epigenetic alterations in the disease, and provide a roadmap to implementation of genome-guided personalized therapy in gastric cancer. The present review discusses the initial studies describing EBV-positive gastric cancer as a distinct clinical entity, presents recently described genetic and epigenetic alterations, and considers potential therapeutic insights derived from the recognition of this new molecular subtype of gastric adenocarcinoma.
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    Petrara, M. R.; Giunco, S.; Serraino, D.; Dolcetti, R.; De Rossi, A. Post-Transplant Lymphoproliferative Disorders: From Epidemiology to Pathogenesis-Driven Treatment. Cancer Lett. 2015, 369 (1), 37– 44,  DOI: 10.1016/j.canlet.2015.08.007
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    Post-transplant lymphoproliferative disorders: From epidemiology to pathogenesis-driven treatment
    Petrara, Maria Raffaella; Giunco, Silvia; Serraino, Diego; Dolcetti, Riccardo; De Rossi, Anita
    Cancer Letters (New York, NY, United States) (2015), 369 (1), 37-44CODEN: CALEDQ; ISSN:0304-3835. (Elsevier)
    Post-transplant lymphoproliferative disorders (PTLDs) represent the most severe complication of both solid organ and hematopoietic stem cell transplantation. The Epstein-Barr Virus (EBV) is the main driver of PTLD, particularly those occurring early after transplantation. EBV-driven malignancies are assocd. with selective expression of latent viral proteins, but uncontrolled lytic replication may favor early phases of cell transformation. Besides immunodepression, persistent immune activation and chronic inflammation play an important role in both virus reactivation and expansion of EBV-infected B cells. EBV-induced immortalization requires the expression of telomerase. TERT, the rate-limiting component of the telomerase complex, is central in the switch from the lytic to the latent viral program, and TERT inhibition induces the EBV lytic cycle and cell death. Immunotherapy and combination of EBV lytic cycle inducers with antiviral drugs are promising strategies to improve the treatment of PTLD patients. This review is aimed at providing an update on the intriguing assocn. between EBV and PTLD, mainly focusing on cases arising after kidney and liver transplantation, which account for the vast majority of transplants.
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    Jaffe, E. S.; Nicolae, A.; Pittaluga, S. Peripheral T-Cell and NK-Cell Lymphomas in the WHO Classification: Pearls and Pitfalls. Mod. Pathol. 2013 261 2013, 26 (1), S71– S87,  DOI: 10.1038/modpathol.2012.181
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    Tse, E.; Kwong, Y. L. The Diagnosis and Management of NK/T-Cell Lymphomas. J. Hematol. Oncol. 2017, 10 (1), 1– 13,  DOI: 10.1186/s13045-017-0452-9
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    Sivachandran, N.; Dawson, C. W.; Young, L. S.; Liu, F.-F.; Middeldorp, J.; Frappier, L. Contributions of the Epstein-Barr Virus EBNA1 Protein to Gastric Carcinoma. J. Virol. 2012, 86 (1), 60– 68,  DOI: 10.1128/JVI.05623-11
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    Contributions of the Epstein-Barr virus EBNA1 protein to gastric carcinoma
    Sivachandran, Nirojini; Dawson, Christopher W.; Young, Lawrence S.; Liu, Fei-Fei; Middeldorp, Jaap; Frappier, Lori
    Journal of Virology (2012), 86 (1), 60-68CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
    Approx. 10% of gastric carcinomas (GC) are comprised of cells latently infected with Epstein-Barr virus (EBV); however, the mechanism by which EBV contributes to the development of this malignancy is unclear. We have investigated the cellular effects of the only EBV nuclear protein expressed in GC, EBNA1, focusing on promyelocytic leukemia (PML) nuclear bodies (NBs), which play important roles in apoptosis, p53 activation, and tumor suppression. AGS GC cells infected with EBV were found to contain fewer PML NBs and less PML protein than the parental EBV-neg. AGS cells, and these levels were restored by silencing EBNA1. Conversely, EBNA1 expression was sufficient to induce the loss of PML NBs and proteins in AGS cells. Consistent with PML functions, EBNA1 expression decreased p53 activation and apoptosis in response to DNA damage and resulted in increased cell survival. In addn., EBNA1 mutants unable to bind CK2 kinase or ubiquitin-specific protease 7 had decreased ability to induce PML loss and to interfere with p53 activation. PML levels in EBV-pos. and EBV-neg. GC biopsy specimens were then compared by immunohistochem. Consistent with the results in the AGS cells, EBV-pos. tumors had significantly lower PML levels than EBV-neg. tumors. The results indicate that EBV infection of GC cells leads to loss of PML NBs through the action of EBNA1, resulting in impaired responses to DNA damage and promotion of cell survival. Therefore, PML disruption by EBNA1 is one mechanism by which EBV may contribute to the development of gastric cancer.
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    Chang, M. S.; Kim, D. H.; Roh, J. K.; Middeldorp, J. M.; Kim, Y. S.; Kim, S.; Han, S.; Kim, C. W.; Lee, B. L.; Kim, W. H.; Woo, J. H. Epstein-Barr Virus-Encoded BARF1 Promotes Proliferation of Gastric Carcinoma Cells through Regulation of NF-ΚB. J. Virol. 2013, 87 (19), 10515– 10523,  DOI: 10.1128/JVI.00955-13
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    Epstein-Barr virus-encoded BARF1 promotes proliferation of gastric carcinoma cells through regulation of NF-κB
    Chang, Mee Soo; Kim, Dong Ha; Roh, Jin Kyung; Middeldorp, Jaap M.; Kim, Yang Soo; Kim, Sunghan; Han, Seungbong; Kim, Chul Woo; Lee, Byung Lan; Kim, Woo Ho; Woo, Jun Hee
    Journal of Virology (2013), 87 (19), 10515-10523CODEN: JOVIAM; ISSN:1098-5514. (American Society for Microbiology)
    In Epstein-Barr virus (EBV)-infected gastric carcinoma, EBV-encoded BARF1 has been hypothesized to function as an oncogene. To evaluate cellular changes induced by BARF1, we isolated the full-length BARF1 gene from gastric carcinoma cells that were naturally infected with EBV and transfected BARF1 into EBV-neg. gastric carcinoma cells. BARF1 protein was primarily secreted into culture supernatant and only marginally detectable within cells. Compared with gastric carcinoma cells contg. empty vector, BARF1-expressing gastric carcinoma cells exhibited increased cell proliferation (P < 0.05). There were no significant differences in apoptosis, invasion, or migration between BARF1-expressing gastric carcinoma cells and empty vector-transfected cells. BARF1-expressing gastric carcinoma cells demonstrated increased nuclear expression of nuclear factor kappa B (NF-κB) RelA protein and increased NF-κB-dependent cyclin D1. The expression of p21WAF1 was diminished by BARF1 transfection and increased by NF-κB inhibition. Proliferation of naturally EBV-infected gastric carcinoma cells was suppressed by BARF1 small interfering RNA (siRNA) (P < 0.05). Immunohistochem. anal. of 120 human gastric carcinoma tissues demonstrated increased expression of cyclin D1 and reduced expression of p21WAF1 in EBV-pos. samples vs. EBV-neg. gastric carcinomas (P < 0.05). In conclusion, the secreted BARF1 may stimulate proliferation of EBV-infected gastric carcinoma cells via upregulation of NF-κB/cyclin D1 and redn. of the cell cycle inhibitor p21WAF1, thereby facilitating EBV-induced cancer progression.
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    Breda, E.; Catarino, R. J. F.; Azevedo, I.; Lobão, M.; Monteiro, E.; Medeiros, R. Epstein-Barr Virus Detection in Nasopharyngeal Carcinoma: Implications in a Low-Risk Area. Braz. J. Otorhinolaryngol. 2010, 76 (3), 310– 315,  DOI: 10.1590/S1808-86942010000300007
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    Epstein-Barr virus detection in nasopharyngeal carcinoma: implications in a low-risk area
    Breda Eduardo; Catarino Raquel Jorge Ferreira; Azevedo Isabel; Lobao Marisa; Monteiro Eurico; Medeiros Rui
    Brazilian journal of otorhinolaryngology (2010), 76 (3), 310-5 ISSN:.
    UNLABELLED: Several studies have been published concerning Epstein-barr virus (EBV) infection and nasopharyngeal cancer (NPC) development. The incidences of histological types are different according to endemic or non-endemic regions. Latent EBV infection is found in almost all cases of NPC in endemic regions, but normally absent in type I carcinomas, more common in non-endemic regions. AIM: The purpose of this hospital-based study was to analyze the presence of EBV in nasopharyngeal tumor tissues and in peripheral blood of nasopharyngeal cancer patients and healthy individuals, in a low risk, non-endemic area. METHODS: EBV detection in samples of nasopharyngeal cancer patients and healthy individuals. RESULTS: This study indicates that the frequency of EBV positive cases in peripheral blood is higher in advanced tumor stages. CONCLUSIONS: The incidence rates of NPC have a distinct distribution. Since the prevalence of this disease is low in occidental countries, little is known about the biology of these tumors in non-endemic areas. We observed statistically significant differences in EBV detection between the NPC patient group and the control group. This study may help to understand the biological mechanisms of NPC and the correlation of EBV infection with this disease, in a low risk, non-endemic region.
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    Chu, E. A.; Wu, J. M.; Tunkel, D. E.; Ishman, S. L. Nasopharyngeal Carcinoma: The Role of the Epstein-Barr Virus. Medscape J. Med. 2008, 10 (7), 165
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    Nasopharyngeal carcinoma: the role of the Epstein-Barr virus
    Chu Eugene A; Wu Julie M; Tunkel David E; Ishman Stacey L
    Medscape journal of medicine (2008), 10 (7), 165 ISSN:.
    Nasopharyngeal carcinoma (NPC) arises from the epithelium of the nasopharynx and is a rare tumor in most parts of the world, including the United States. Neck swelling, nasal obstruction, and epistaxis are the most common presenting symptoms. The etiology of NPC is multifactorial and includes genetic susceptibility, exposure to carcinogens, and prior infection with the Epstein-Barr virus (EBV). We report a case of a 16-year-old African-American male who presented with hemoptysis and a 3-month history of a neck mass. Diagnostic evaluation identified a nasopharyngeal mass that upon biopsy was shown to be an undifferentiated nasopharyngeal carcinoma with immunohistochemical stains markedly positive for EBV. Recent studies have further elucidated the role of EBV in the pathogenesis of NPC and have demonstrated the utility of EBV studies in staging, prognosis, and post-therapeutic monitoring.
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    Shinozaki-Ushiku, A.; Kunita, A.; Fukayama, M. Update on Epstein-Barr Virus and Gastric Cancer (Review). Int. J. Oncol. 2015, 46 (4), 1421– 1434,  DOI: 10.3892/ijo.2015.2856
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    Update on Epstein-Barr virus and gastric cancer (Review)
    Shinozaki-Ushiku, Aya; Kunita, Akiko; Fukayama, Masashi
    International Journal of Oncology (2015), 46 (4), 1421-1434CODEN: IJONES; ISSN:1791-2423. (Spandidos Publications Ltd.)
    Epstein-Barr virus-assocd. gastric carcinoma (EBVaGC) is a distinct subtype that accounts for nearly 10% of gastric carcinomas. EBVaGC is defined by monoclonal proliferation of carcinoma cells with latent EBV infection, as demonstrated by EBV-encoded small RNA (EBER) in situ hybridization. EBVaGC has characteristic clinicopathol. features, including predominance among males, a proximal location in the stomach, lymphoepithelioma-like histol. and a favorable prognosis. EBVaGC belongs to latency type I or II, in which EBERs, EBNA-1, BARTs, LMP-2A and BART miRNAs are expressed. Previous studies have shown that some EBV latent genes have oncogenic properties. Recent advances in genome-wide and comprehensive mol. analyses have demonstrated that both genetic and epigenetic changes contribute to EBVaGC carcinogenesis. Genetic changes that are characteristic of EBVaGC include frequent mutations in PIK3CA and ARID1A and amplification of JAK2 and PD-L1/L2. Global CpG island hypermethylation, which induces epigenetic silencing of tumor suppressor genes, is also a unique feature of EBVaGC and is considered to be crucial for its carcinogenesis. Furthermore, post-transcriptional gene expression regulation by cellular and/or EBV-derived microRNAs has attracted considerable attention. These abnormalities result in significant alterations in gene expression related to cell proliferation, apoptosis, migration and immune signaling pathways. In the present review we highlight the latest findings on EBVaGC from clinicopathol. and mol. perspectives to provide a better understanding of EBV involvement in gastric carcinogenesis.
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    Fukuda, M.; Ikuta, K.; Yanagihara, K.; Tajima, M.; Kuratsune, H.; Kurata, T.; Sairenji, T. Effect of Transforming Growth Factor-Beta1 on the Cell Growth and Epstein-Barr Virus Reactivation in EBV-Infected Epithelial Cell Lines. Virology 2001, 288 (1), 109– 118,  DOI: 10.1006/viro.2001.1071
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    Effect of Transforming Growth Factor-β1 on the Cell Growth and Epstein-Barr Virus Reactivation in EBV-Infected Epithelial Cell Lines
    Fukuda, Makoto; Ikuta, Kazufumi; Yanagihara, Kazuyoshi; Tajima, Masako; Kuratsune, Hirohiko; Kurata, Takeshi; Sairenji, Takeshi
    Virology (2001), 288 (1), 109-118CODEN: VIRLAX; ISSN:0042-6822. (Academic Press)
    Transforming growth factor (TGF)-β1 is a multi-functional cytokine that plays important roles in regulating cell growth and differentiation in many biol. systems. In this study, we found that gastric tissue-derived Epstein-Barr virus (EBV)-infected epithelial cell lines GT38 and GT39 had resistance to TGF-β1-mediated growth inhibition and apoptosis compared to a TGF-β1-susceptible gastric carcinoma cell line HSC-39. However, TGF-β1 partially induced EBV reactivation in GT38 and GT39 cells, as shown by the induction of EBV immediate-early BZLF1 RNA and its protein product ZEBRA and early antigen-D. The expressions of TGF-β receptor I and II were detected in GT38 and GT39 cells by Northern and Western blot analyses. Both cell lines spontaneously produced the TGF-β1, which was sufficient for inhibiting cell growth of HSC-39 cells. Taken together, these data suggest that TGF-β1 may be a key factor for EBV reactivation and selective growth of EBV-infected epithelial cells in vivo. (c) 2001 Academic Press.
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    Hino, R.; Uozaki, H.; Inoue, Y.; Shintani, Y.; Ushiku, T.; Sakatani, T.; Takada, K.; Fukayama, M. Survival Advantage of EBV-Associated Gastric Carcinoma: Survivin up-Regulation by Viral Latent Membrane Protein 2A. Cancer Res. 2008, 68 (5), 1427– 1435,  DOI: 10.1158/0008-5472.CAN-07-3027
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    Survival Advantage of EBV-Associated Gastric Carcinoma: Survivin Up-regulation by Viral Latent Membrane Protein 2A
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    Cancer Research (2008), 68 (5), 1427-1435CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
    EBV-assocd. gastric carcinoma is a distinct subset of gastric carcinoma infected with EBV, which shows latency I type expression of EBV latent genes (EBNA1, EBER, BARF0, and LMP2A). To clarify the role of EBV in this type of gastric carcinoma, the cell biol. characteristics (growth, apoptosis, and migration) were evaluated in gastric carcinoma cell lines (MKN-1, TMK1, MKN-74 and MKN-7) with and without infection of recombinant EBV harboring the neomycin resistance gene. The infection reiterated the latency I type infection, and the only difference obsd. in EBV-infected gastric carcinoma cell lines was the resistance to serum deprivation-induced apoptosis. Comparative analyses of transcripts of apoptosis-assocd. genes in MKN-1 and EBV-MKN-1 and subsequent quant. reverse transcription-PCR anal. showed up-regulation of the cellular survivin gene in EBV-infected gastric carcinoma cell lines. Small interfering RNA-mediated knockdown of survivin increased apoptosis in EBV-MKN-1 to the level of the original MKN-1 cells. Transfection of EBV-latent genes into MKN-1 showed that LMP2A, but not EBNA1, EBER, or BARF0, up-regulated survivin gene expression. LMP2A-mediated survivin up-regulation in gastric carcinoma cells was inhibited with a nuclear factor-κB (NF-κB) inhibitor, Bay 11-7082. In parallel with these findings in vitro, survivin expression was frequent in carcinoma tissues of gastric carcinoma by immunohistochem., and significantly more in EBV-assocd. gastric carcinoma (12 of 13) than in EBV-neg. gastric carcinoma in the advanced stage (P = 0.0307). Thus, EBV uses its latent protein, LMP2A, to activate the NF-κB-survivin pathway to rescue EBV-infected epithelial cells from serum deprivation, and up-regulation of survivin may play a role in the progression of this specific type of gastric carcinoma infected with EBV.
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    Liu, X.; Gao, Y.; Luo, B.; Zhao, Y. Construction and Antiapoptosis Activities of Recombinant Adenoviral Expression Vector Carrying EBV Latent Membrane Protein 2A. Gastroenterol. Res. Pract. 2011, 2011, 1,  DOI: 10.1155/2011/182832
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    Seeger, C.; Mason, W. S. Hepatitis B Virus Biology. Microbiol. Mol. Biol. Rev. 2000, 64 (1), 51– 68,  DOI: 10.1128/MMBR.64.1.51-68.2000
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    Hepatitis B virus biology
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    Microbiology and Molecular Biology Reviews (2000), 64 (1), 51-68CODEN: MMBRF7; ISSN:1092-2172. (American Society for Microbiology)
    A review with 255 refs.
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    Woodman, C. B. J.; Collins, S. I.; Young, L. S. The Natural History of Cervical HPV Infection: Unresolved Issues. Nat. Rev. Cancer 2007, 7 (1), 11– 22,  DOI: 10.1038/nrc2050
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    The natural history of cervical HPV infection: unresolved issues
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    Nature Reviews Cancer (2007), 7 (1), 11-22CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)
    The identification of high-risk human papillomavirus (HPV) types as a necessary cause of cervical cancer offers the prospect of effective primary prevention and the possibility of improving the efficiency of cervical screening programs. However, for these opportunities to be realized, a more complete understanding of the natural history of HPV infection, and its relationship to the development of epithelial abnormalities of the cervix, is required. We discuss areas of uncertainty, and their possible effect on disease prevention strategies.
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    Doorbar, J. Molecular Biology of Human Papillomavirus Infection and Cervical Cancer. Clin. Sci. (Lond). 2006, 110 (5), 525– 541,  DOI: 10.1042/CS20050369
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    Molecular biology of human papillomavirus infection and cervical cancer
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    Clinical science (London, England : 1979) (2006), 110 (5), 525-41 ISSN:0143-5221.
    HPVs (human papillomaviruses) infect epithelial cells and cause a variety of lesions ranging from common warts/verrucas to cervical neoplasia and cancer. Over 100 different HPV types have been identified so far, with a subset of these being classified as high risk. High-risk HPV DNA is found in almost all cervical cancers (>99.7%), with HPV16 being the most prevalent type in both low-grade disease and cervical neoplasia. Productive infection by high-risk HPV types is manifest as cervical flat warts or condyloma that shed infectious virions from their surface. Viral genomes are maintained as episomes in the basal layer, with viral gene expression being tightly controlled as the infected cells move towards the epithelial surface. The pattern of viral gene expression in low-grade cervical lesions resembles that seen in productive warts caused by other HPV types. High-grade neoplasia represents an abortive infection in which viral gene expression becomes deregulated, and the normal life cycle of the virus cannot be completed. Most cervical cancers arise within the cervical transformation zone at the squamous/columnar junction, and it has been suggested that this is a site where productive infection may be inefficiently supported. The high-risk E6 and E7 proteins drive cell proliferation through their association with PDZ domain proteins and Rb (retinoblastoma), and contribute to neoplastic progression, whereas E6-mediated p53 degradation prevents the normal repair of chance mutations in the cellular genome. Cancers usually arise in individuals who fail to resolve their infection and who retain oncogene expression for years or decades. In most individuals, immune regression eventually leads to clearance of the virus, or to its maintenance in a latent or asymptomatic state in the basal cells.
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    Mesri, E. A.; Cesarman, E.; Boshoff, C. Kaposi’s Sarcoma and Its Associated Herpesvirus. Nat. Rev. Cancer 2010, 10 (10), 707– 719,  DOI: 10.1038/nrc2888
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    Kaposi's sarcoma and its associated herpesvirus
    Mesri, Enrique A.; Cesarman, Ethel; Boshoff, Chris
    Nature Reviews Cancer (2010), 10 (10), 707-719CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)
    A review. Kaposi's sarcoma (KS) is the most common cancer in HIV-infected untreated individuals. Kaposi's sarcoma-assocd. herpesvirus (KSHV; also known as human herpesvirus 8 (HHV8)) is the infectious cause of this neoplasm. In this Review we describe the epidemiol. of KS and KSHV, and the insights into the remarkable mechanisms through which KSHV can induce KS that have been gained in the past 16 years. KSHV latent transcripts, such as latency-assocd. nuclear antigen (LANA), viral cyclin, viral FLIP and viral-encoded microRNAs, drive cell proliferation and prevent apoptosis, whereas KSHV lytic proteins, such as viral G protein-coupled receptor, K1 and virally encoded cytokines (viral interleukin-6 and viral chemokines) further contribute to the unique angioproliferative and inflammatory KS lesions through a mechanism called paracrine neoplasia.
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    Young, L. S.; Rickinson, A. B. Epstein-Barr Virus: 40 Years On. Nat. Rev. Cancer 2004, 4 (10), 757– 768,  DOI: 10.1038/nrc1452
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    Epstein-Barr virus: 40 years on
    Young, Lawrence S.; Rickinson, Alan B.
    Nature Reviews Cancer (2004), 4 (10), 757-768CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)
    A review. Epstein-Barr virus (EBV) was discovered 40 yr ago from examg. electron micrographs of cells cultured from Burkitt's lymphoma, a childhood tumor that is common in sub-Saharan Africa, where its unusual geog. distribution - which matches that of holoendemic malaria - indicated a viral etiol. However, far from showing a restricted distribution, EBV - a γ-herpesvirus - was found to be widespread in all human populations and to persist in the vast majority of individuals as a lifelong, asymptomatic infection of the B-lymphocyte pool. Despite such ubiquity, the link between EBV and 'endemic' Burkitt's lymphoma proved consistent and became the first of an unexpectedly wide range of assocns. discovered between this virus and tumors.
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    Shi, G.; Suzuki, T. Molecular Basis of Encapsidation of Hepatitis C Virus Genome. Front. Microbiol. 2018, 9 (MAR), 396,  DOI: 10.3389/fmicb.2018.00396
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    Molecular Basis of Encapsidation of Hepatitis C Virus Genome
    Shi Guoli; Suzuki Tetsuro
    Frontiers in microbiology (2018), 9 (), 396 ISSN:1664-302X.
    Hepatitis C virus (HCV), a major etiologic agent of human liver diseases, is a positive-sense single-stranded RNA virus and is classified in the Flaviviridae family. Although research findings for the assembly of HCV particles are accumulating due to development of HCV cell culture system, the mechanism(s) by which the HCV genome becomes encapsidated remains largely unclear. In general, viral RNA represents only a small fraction of the RNA molecules in the cells infected with RNA viruses, but the viral genomic RNA is considered to selectively packaged into virions. It was recently demonstrated that HCV RNAs containing 3' end of the genome are selectively incorporated into virus particles during the assembly process and the 3' untranslated region functions as a cis-acting element for RNA packaging. Here, we discuss the molecular basis of RNA encapsidation of HCV and classical flaviviruses, contrast with the packaging mechanism of HIV-1.
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    Kannian, P.; Green, P. L. Human T Lymphotropic Virus Type 1 (HTLV-1): Molecular Biology and Oncogenesis. Viruses 2010, 2 (9), 2037,  DOI: 10.3390/v2092037
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    Human T lymphotropic virus type 1 (HTLV-1): molecular biology and oncogenesis
    Kannian, Priya; Green, Patrick L.
    Viruses (2010), 2 (), 2037-2077CODEN: VIRUBR; ISSN:1999-4915. (Molecular Diversity Preservation International)
    A review. Human T lymphotropic viruses (HTLVs) are complex deltaretroviruses that do not contain a proto-oncogene in their genome, yet are capable of transforming primary T lymphocytes both in vitro and in vivo. There are four known strains of HTLV including HTLV type 1 (HTLV-1), HTLV-2, HTLV-3 and HTLV-4. HTLV-1 is primarily assocd. with adult T cell leukemia (ATL) and HTLV-1-assocd. myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-2 is rarely pathogenic and is sporadically assocd. with neurol. disorders. There have been no diseases assocd. with HTLV-3 or HTLV-4 to date. Due to the difference in the disease manifestation between HTLV-1 and HTLV-2, a clear understanding of their individual pathobiologies and the role of various viral proteins in transformation should provide insights into better prognosis and prevention strategies. In this review, we aim to summarize the data accumulated so far in the transformation and pathogenesis of HTLV-1, focusing on the viral Tax and HBZ and citing appropriate comparisons to HTLV-2.
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    Stevenson, M. HIV-1 Pathogenesis. Nat. Med. 2003, 9 (7), 853– 860,  DOI: 10.1038/nm0703-853
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    HIV-1 pathogenesis
    Stevenson, Mario
    Nature Medicine (New York, NY, United States) (2003), 9 (7), 853-860CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
    A review. Despite considerable advances in HIV science in the past 20 yr, the reason why HIV-1 infection is pathogenic is still debated and the goal of eradicating HIV-1 infection remains elusive. A deeper understanding of the interplay between HIV-1 and its host and why simian immunodeficiency virus (SIV) is nonpathogenic in some natural hosts may provide a few answers. Topics discussed include virus-host interactions at the mol. level; and elements of viral pathogenicity.
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    Mui, U. N.; Haley, C. T.; Tyring, S. K. Viral Oncology: Molecular Biology and Pathogenesis. J. Clin. Med. 2017, 6 (12), 111,  DOI: 10.3390/jcm6120111
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    Viral oncology: molecular biology and pathogenesis
    Mui, Uyen Ngoc; Haley, Christopher T.; Tyring, Stephen K.
    Journal of Clinical Medicine (2017), 6 (12), 111/1-111/58CODEN: JCMOHK; ISSN:2077-0383. (MDPI AG)
    Oncoviruses are implicated in approx. 12% of all human cancers. A large no. of the world's population harbors at least one of these oncoviruses, but only a small proportion of these individuals go on to develop cancer. The interplay between host and viral factors is a complex process that works together to create a microenvironment conducive to oncogenesis. In this review, the mol. biol. and oncogenic pathways of established human oncoviruses will be discussed. Currently, there are seven recognized human oncoviruses, which include Epstein-Barr Virus (EBV), Human Papillomavirus (HPV), Hepatitis B and C viruses (HBV and HCV), Human T-cell lymphotropic virus-1 (HTLV-1), Human Herpesvirus-8 (HHV-8), and Merkel Cell Polyomavirus (MCPyV). Available and emerging therapies for these oncoviruses will be mentioned.
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    Shuda, M.; Feng, H.; Kwun, H. J.; Rosen, S. T.; Gjoerup, O.; Moore, P. S.; Chang, Y. T Antigen Mutations Are a Human Tumor-Specific Signature for Merkel Cell Polyomavirus. Proc. Natl. Acad. Sci. U. S. A. 2008, 105 (42), 16272– 16277,  DOI: 10.1073/pnas.0806526105
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    T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus
    Shuda, Masahiro; Feng, Huichen; Kwun, Hyun Jin; Rosen, Steven T.; Gjoerup, Ole; Moore, Patrick S.; Chang, Yuan
    Proceedings of the National Academy of Sciences of the United States of America (2008), 105 (42), 16272-16277CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Merkel cell polyomavirus (MCV) is a virus discovered in our lab. at the University of Pittsburgh that is monoclonally integrated into the genome of ≈80% of human Merkel cell carcinomas (MCCs). Transcript mapping was performed to show that MCV expresses transcripts in MCCs similar to large T (LT), small T (ST), and 17kT transcripts of SV40. Nine MCC tumor-derived LT genomic sequences have been examd., and all were found to harbor mutations prematurely truncating the MCV LT helicase. In contrast, four presumed episomal viruses from nontumor sources did not possess this T antigen signature mutation. Using coimmunopptn. and origin replication assays, we show that tumor-derived virus mutations do not affect retinoblastoma tumor suppressor protein (Rb) binding by LT but do eliminate viral DNA replication capacity. Identification of an MCC cell line (MKL-1) having monoclonal MCV integration and the signature LT mutation allowed us to functionally test both tumor-derived and wild type (WT) T antigens. Only WT LT expression activates replication of integrated MCV DNA in MKL-1 cells. Our findings suggest that MCV-pos. MCC tumor cells undergo selection for LT mutations to prevent autoactivation of integrated virus replication that would be detrimental to cell survival. Because these mutations render the virus replication-incompetent, MCV is not a "passenger virus" that secondarily infects MCC tumors.
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    Bodaghi, S.; Comoli, P.; Bösch, R.; Azzi, A.; Gosert, R.; Leuenberger, D.; Ginevri, F.; Hirsch, H. H. Antibody Responses to Recombinant Polyomavirus BK Large T and VP1 Proteins in Young Kidney Transplant Patients. J. Clin. Microbiol. 2009, 47 (8), 2577– 2585,  DOI: 10.1128/JCM.00030-09
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    Antibody responses to recombinant polyomavirus BK large T and VP1 proteins in young kidney transplant patients
    Bodaghi, Sohrab; Comoli, Patrizia; Bosch, Robert; Azzi, Alberta; Gosert, Rainer; Leuenberger, David; Ginevri, Fabrizio; Hirsch, Hans H.
    Journal of Clinical Microbiology (2009), 47 (8), 2577-2585CODEN: JCMIDW; ISSN:0095-1137. (American Society for Microbiology)
    BK virus (BKV)-specific immunity is crit. for polyomavirus-assocd. nephropathy, but antibody responses are incompletely defined. We compared the hemagglutination inhibition assay (HIA) with IgG enzyme immunoassays (EIA) to BKV proteins expressed in baculovirus-infected insect cells. N-terminal, internal, and C-terminal domains of the BKV large T antigen (BKLT) were fused to glutathione S-transferase (GST), yielding GST-BKLTD1, GST-BKLTD2, and GST-BKLTD3, resp. The BKV capsid VP1 was expressed as a GST fusion (BKVP1) or as a native VP1 assembled into viruslike particles (BKVLP). We tested 422 sera from 28 healthy donors (HD), 99 dialysis patients (DP; median age, 15 years; range, 3 to 32 years), and 46 age-matched kidney transplant patients (KTP; median age, 15 years; range, 2 to 33 years). In HD, HIA and BKVLP EIA both yielded a 91.7% seroreactivity, whereas all other EIA responses were lower (BKVP1, 83.3%; BKLTD1, 25%; BKLTD2, 29%; BKLTD3, 40%). HIA titers significantly correlated with EIA levels for BKVLP, BKVP1, and BKLTD1 but not for BKLTD2 or BKLTD3, which were barely above the cutoff. In DP, the seroreactivities of HIA, BKVLP, and BKLTD1 were lower than that in HD (63.6%, 86.9%, and 10.1%, resp.) and they had lower titers (P < 0.001). In KTP, seropositivities for BKVLP, BKVP1, and BKLTD1 were 78%, 50%, and 17%, resp., but anti-BKVLP levels increased significantly in KTP with viruria and viremia, whereas anti-BKLTD1 levels increased after clearing sustained BKV viremia. In conclusion, anti-BKVLP is equiv. to HIA in HD but is more sensitive to det. the BKV serostatus in DP and KTP. In KTP, anti-BKVLP responds to recent BKV viruria and viremia, whereas anti-BKLTD1 may indicate emerging BKV-specific immune control.
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    Tolstov, Y. L.; Pastrana, D. V.; Feng, H.; Becker, J. C.; Jenkins, F. J.; Moschos, S.; Chang, Y.; Buck, C. B.; Moore, P. S. Human Merkel Cell Polyomavirus Infection II. MCV Is a Common Human Infection That Can Be Detected by Conformational Capsid Epitope Immunoassays. Int. J. Cancer 2009, 125 (6), 1250,  DOI: 10.1002/ijc.24509
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    Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays
    Tolstov, Yanis L.; Pastrana, Diana V.; Feng, Huichen; Becker, Juergen C.; Jenkins, Frank J.; Moschos, Stergios; Chang, Yuan; Buck, Christopher B.; Moore, Patrick S.
    International Journal of Cancer (2009), 125 (6), 1250-1256CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)
    Merkel cell polyomavirus (MCV) is a newly-discovered human tumor virus found in ∼80% of Merkel cell carcinoma (MCC). The rate of MCV infection among persons without MCC is unknown. We developed a MCV virus-like particle (VLP) enzyme-linked immunoassay (EIA) that does not cross-react with human BK or murine polyomaviruses. Peptide mapping of the MCV VP1 gene and immunoblotting with denatured MCV VLP are less sensitive than the MCV EIA in detecting MCV antibodies suggesting antibody reactivity in this assay primarily targets conformational but not linear epitopes. Among MCC patients, all 21 (100%) patients tested with MCV-pos. tumors had high serum MCV IgG but not high MCV IgM levels. Only 3 of 6 (50%) MCC patients with MCV-neg. tumors were pos. for MCV antibodies. Sera from most adults, including 107 of 166 (64%) blood donors, 63 of 100 (63%) com. donors and 37 of 50 (74%) systemic lupus erythematosus patients, show evidence for prior MCV exposure. Age-specific MCV prevalence was detd. by examg. a cross-sectional distribution of 150 Langerhans cell histiocytosis (an unrelated neoplasm) patient sera. MCV prevalence increases from 50% among children age 15 years or younger to 80% among persons older than 50 years. We did not find evidence for vertical transmission among infants. Although past exposure to MCV is common among all adult groups, MCC patients have a markedly elevated MCV IgG response compared with control patients. Our study demonstrates that MCV is a widespread but previously unrecognized human infection. © 2009 UICC.
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    Pastrana, D. V.; Tolstov, Y. L.; Becker, J. C.; Moore, P. S.; Chang, Y.; Buck, C. B. Quantitation of Human Seroresponsiveness to Merkel Cell Polyomavirus. PLoS Pathog. 2009, 5 (9), e1000578,  DOI: 10.1371/journal.ppat.1000578
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    Arora, R.; Chang, Y.; Moore, P. S. MCV and Merkel Cell Carcinoma: A Molecular Success Story. Curr. Opin. Virol. 2012, 2 (4), 489– 498,  DOI: 10.1016/j.coviro.2012.05.007
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    MCV and Merkel cell carcinoma: a molecular success story
    Arora, Reety; Chang, Yuan; Moore, Patrick S.
    Current Opinion in Virology (2012), 2 (4), 489-498CODEN: COVUAF; ISSN:1879-6257. (Elsevier B. V.)
    A review. Merkel cell polyomavirus (MCV), discovered in 2008, is clonally integrated in ∼80% Merkel cell carcinoma (MCC). MCV is a common skin flora and initiates cancer in susceptible hosts only after it acquires a precise set of mutations that render it replication incompetent. Both MCV large and small T proteins promote cancer cell survival and proliferation. Large T targets pocket proteins regulating cell cycle transit while small T activates cap-dependent translation crit. for cancer cell growth. These findings already have led to new diagnostics and clin. trials to target MCV-induced survivin and to promote antitumor immunity. In four years, the cause, diagnosis and therapy for an intractable cancer has been changed due to the mol. discovery of MCV.
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    Lewis, J. S.; Duncavage, E.; Klonowski, P. W. Oral Cavity Neuroendocrine Carcinoma: A Comparison Study with Cutaneous Merkel Cell Carcinoma and Other Mucosal Head and Neck Neuroendocrine Carcinomas. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2010, 110 (2), 209– 217,  DOI: 10.1016/j.tripleo.2010.04.007
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    95
    Oral cavity neuroendocrine carcinoma: a comparison study with cutaneous Merkel cell carcinoma and other mucosal head and neck neuroendocrine carcinomas
    Lewis James S Jr; Duncavage Eric; Klonowski Paul W
    Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics (2010), 110 (2), 209-17 ISSN:.
    OBJECTIVES: Published cases of oral high-grade neuroendocrine carcinoma (HGNEC) variably call the tumors Merkel cell carcinoma (MCC) or small-cell/high-grade neuroendocrine carcinoma. We studied cases of cutaneous MCC and mucosal HGNEC to better distinguish them and to better define oral cases. STUDY DESIGN: Twelve cutaneous MCC and 14 mucosal HGNEC cases were identified. We reviewed the hematoxylin-eosin (H&E) morphology and performed immunohistochemistry for cytokeratin 20 (CK20), thyroid transcription factor 1 (TTF-1), p63, neurofilament (NF), and achaete-scute homolog 1 (MASH-1). We also performed polymerase chain reaction (PCR) for the Merkel cell polyomavirus (MCPyV). RESULTS: By morphology and immunohistochemistry, MCC and HGNEC showed many differences. CK20, NF, and TTF-1 stains were the most discriminatory. MASH-1 was expressed by both MCC and HGNEC. MCPyV was present in MCC and absent in all HGNEC. The 2 oral cavity mucosal carcinomas segregated into MCC and HGNEC types, the former having the H&E nuclear morphology and classic dot-like perinuclear CK20 staining typically associated with MCC. CONCLUSIONS: Oral cavity neuroendocrine carcinoma can be segregated into MCC and small-cell/HGNEC types by morphology and CK20 immunohistochemistry. MCPyV was present by PCR in cutaneous MCC but was not found in mucosal HGNEC.
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    Paik, J. Y.; Hall, G.; Clarkson, A.; Lee, L.; Toon, C.; Colebatch, A.; Chou, A.; Gill, A. J. Immunohistochemistry for Merkel Cell Polyomavirus Is Highly Specific but Not Sensitive for the Diagnosis of Merkel Cell Carcinoma in the Australian Population. Hum. Pathol. 2011, 42 (10), 1385– 1390,  DOI: 10.1016/j.humpath.2010.12.013
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    Immunohistochemistry for Merkel cell polyomavirus is highly specific but not sensitive for the diagnosis of Merkel cell carcinoma in the Australian population
    Paik Julie Y; Hall Geoffrey; Clarkson Adele; Lee Lianne; Toon Christopher; Colebatch Andrew; Chou Angela; Gill Anthony J
    Human pathology (2011), 42 (10), 1385-90 ISSN:.
    Recent studies have demonstrated a high frequency of detection of Merkel cell polyomavirus in Merkel cell carcinoma. However, most of these studies are from European or North American centers that have relatively low sun exposure and may have a higher incidence of virus-driven oncogenesis compared with the highly sun-exposed but predominantly fair-skinned Australian population. We performed immunohistochemistry for Merkel cell polyomavirus on 104 cases of Merkel cell carcinoma and 74 cases of noncutaneous small cell-undifferentiated carcinoma from 3 major Australian centers. Nineteen (18.3%) cases of Merkel cell carcinoma showed positive staining for Merkel cell polyomavirus versus 1 (1.3%) of small cell-undifferentiated carcinoma. All 15 cases (14.3%) of Merkel cell carcinoma with areas of mixed squamous differentiation showed negative staining. We found positive staining in only 3 (7.7%) of 39 Merkel cell carcinoma from the head and neck (the most sun-exposed area) versus 16 (24.6%) of 65 of tumors from other sites (P < .05). Our findings support the concept of a Merkel cell polyomavirus-driven and a non-Merkel cell polyomavirus-driven (primarily sun-dependent) pathway in Merkel cell carcinoma carcinogenesis, with the latter being significantly more frequent in Australia and in mixed squamous-Merkel cell carcinoma (which is also more frequent in Australia). Although immunohistochemistry for Merkel cell polyomavirus seems to be highly specific in all populations, the low incidence of Merkel cell polyomavirus-positive Merkel cell carcinoma in a highly sun-exposed population limits its diagnostic utility in this setting.
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  97. 97
    Lemos, B. D.; Storer, B. E.; Iyer, J. G.; Phillips, J. L.; Bichakjian, C. K.; Fang, L. C.; Johnson, T. M.; Liegeois-Kwon, N. J.; Otley, C. C.; Paulson, K. G.; Ross, M. I.; Yu, S. S.; Zeitouni, N. C.; Byrd, D. R.; Sondak, V. K.; Gershenwald, J. E.; Sober, A. J.; Nghiem, P. Pathologic Nodal Evaluation Improves Prognostic Accuracy in Merkel Cell Carcinoma: Analysis of 5823 Cases as the Basis of the First Consensus Staging System. J. Am. Acad. Dermatol. 2010, 63 (5), 751– 761,  DOI: 10.1016/j.jaad.2010.02.056
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    97
    Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system
    Lemos Bianca D; Storer Barry E; Iyer Jayasri G; Phillips Jerri Linn; Bichakjian Christopher K; Fang L Christine; Johnson Timothy M; Liegeois-Kwon Nanette J; Otley Clark C; Paulson Kelly G; Ross Merrick I; Yu Siegrid S; Zeitouni Nathalie C; Byrd David R; Sondak Vernon K; Gershenwald Jeffrey E; Sober Arthur J; Nghiem Paul
    Journal of the American Academy of Dermatology (2010), 63 (5), 751-61 ISSN:.
    BACKGROUND: The management of Merkel cell carcinoma (MCC) has been complicated by a lack of detailed prognostic data and by the presence of conflicting staging systems. OBJECTIVE: We sought to determine the prognostic significance of tumor size, clinical versus pathologic nodal evaluation, and extent of disease at presentation and thereby derive the first consensus staging/prognostic system for MCC. METHODS: A total of 5823 prospectively enrolled MCC cases from the National Cancer Data Base had follow-up data (median 64 months) and were used for prognostic analyses. RESULTS: At 5 years, overall survival was 40% and relative survival (compared with age- and sex-matched population data) was 54%. Among all MCC cases, 66% presented with local, 27% with nodal, and 7% with distant metastatic disease. For cases presenting with local disease only, smaller tumor size was associated with better survival (stage I, ≤2 cm, 66% relative survival at 5 years; stage II, >2 cm, 51%; P < .0001). Patients with clinically local-only disease and pathologically proven negative nodes had better outcome (76% at 5 years) than those who only underwent clinical nodal evaluation (59%, P < .0001). LIMITATIONS: The National Cancer Data Base does not capture disease-specific survival. Overall survival for patients with MCC was therefore used to calculate relative survival based on matched population data. CONCLUSION: Although the majority (68%) of patients with MCC in this nationwide cohort did not undergo pathologic nodal evaluation, this procedure may be indicated in many cases as it improves prognostic accuracy and has important treatment implications for those found to have microscopic nodal involvement.
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  98. 98
    Deneve, J. L.; Messina, J. L.; Marzban, S. S.; Gonzalez, R. J.; Walls, B. M.; Fisher, K. J.; Chen, Y. A.; Cruse, C. W.; Sondak, V. K.; Zager, J. S. Merkel Cell Carcinoma of Unknown Primary Origin. Ann. Surg. Oncol. 2012, 19 (7), 2360– 2366,  DOI: 10.1245/s10434-011-2213-2
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    98
    Merkel cell carcinoma of unknown primary origin
    Deneve Jeremiah L; Messina Jane L; Marzban Suroosh S; Gonzalez Ricardo J; Walls Brooke M; Fisher Kate J; Chen Y Ann; Cruse C Wayne; Sondak Vernon K; Zager Jonathan S
    Annals of surgical oncology (2012), 19 (7), 2360-6 ISSN:.
    BACKGROUND: Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin. MCC from an unknown primary origin (MCCUP) can present a diagnostic and therapeutic challenge. We describe our single-institution experience with the diagnosis and management of MCCUP presenting as metastases to lymph nodes. METHODS: After institutional review board approval, our institutional database spanning the years 1998-2010 was queried for patients with MCCUP. Clinicopathologic variables and outcomes were assessed. RESULTS: From a database of 321 patients with MCC, 38 (12%) were identified as having nodal MCCUP. Median age was 67 years, and 79% were men. Nodal basins involved at presentation were cervical (58%), axillary/epitrochlear (21%), or inguinal/iliac (21%). CK20 staining was positive in 93% of tumors tested, and all were negative for thyroid transcription factor-1. Twenty-nine patients (76%) underwent complete regional lymph node dissection (LND): 3 had LND alone, ten had LND and adjuvant radiotherapy, and 16 underwent LND followed by chemoradiotherapy. Definitive chemoradiotherapy without surgery was provided to six patients (16%), while radiotherapy alone was provided to three (8%). Recurrence was observed in 34% of patients. Median recurrence-free survival was 35 months. Ten patients (26%) died, five of disease and five of other causes. The median overall survival was 104 months. CONCLUSIONS: Nodal MCCUP is a rare disease affecting primarily elderly white men. Recurrence is observed in approximately one-third of patients, with a 104 month median overall survival after a multimodal treatment approach consisting of surgery along with adjuvant chemotherapy and radiotherapy in the majority of patients.
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  99. 99
    Feng, H.; Shuda, M.; Chang, Y.; Moore, P. S. Clonal Integration of a Polyomavirus in Human Merkel Cell Carcinoma. Science 2008, 319 (5866), 1096– 1100,  DOI: 10.1126/science.1152586
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    99
    Clonal Integration of a Polyomavirus in Human Merkel Cell Carcinoma
    Feng, Huichen; Shuda, Masahiro; Chang, Yuan; Moore, Patrick S.
    Science (Washington, DC, United States) (2008), 319 (5866), 1096-1100CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Merkel cell carcinoma (MCC) is a rare but aggressive human skin cancer that typically affects elderly and immunosuppressed individuals, a feature suggestive of an infectious origin. The authors studied MCC samples by digital transcriptome subtraction and detected a fusion transcript between a previously undescribed virus T antigen and a human receptor tyrosine phosphatase. Further investigation led to identification and sequence anal. of the 5387-base-pair genome of a previously unknown polyomavirus that we call Merkel cell polyomavirus (MCV or MCPyV). MCV sequences were detected in 8 of 10 (80%) MCC tumors but only 5 of 59 (8%) control tissues from various body sites and 4 of 25 (16%) control skin tissues. In six of eight MCV-pos. MCCs, viral DNA was integrated within the tumor genome in a clonal pattern, suggesting that MCV infection and integration preceded clonal expansion of the tumor cells. Thus, MCV may be a contributing factor in the pathogenesis of MCC.
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  100. 100
    Kassem, A.; Schöpflin, A.; Diaz, C.; Weyers, W.; Stickeler, E.; Werner, M.; Zur Hausen, A. Frequent Detection of Merkel Cell Polyomavirus in Human Merkel Cell Carcinomas and Identification of a Unique Deletion in the VP1 Gene. Cancer Res. 2008, 68 (13), 5009– 5013,  DOI: 10.1158/0008-5472.CAN-08-0949
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    100
    Frequent detection of Merkel cell polyomavirus in human merkel cell carcinomas and identification of a unique deletion in the VP1 gene
    Kassem, Ahmad; Schoepflin, Anja; Diaz, Carlos; Weyers, Wolfgang; Stickeler, Elmar; Werner, Martin; zur Hausen, Axel
    Cancer Research (2008), 68 (13), 5009-5013CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
    Merkel cell carcinoma (MCC) is a rare but very aggressive human malignancy of the elderly or immunosuppressed patients. Recently, the clonal integration of a new human polyoma virus, which was termed Merkel cell polyomavirus (MCPyV), has been reported in 8 of 10 MCC patients. In the present study, we studied the formalin-fixed and paraffin-embedded tissue specimens of 39 MCC for the presence of MCPyV by PCR. We applied four different primer sets directed against the large T antigen and the VP1 gene of MCPyV. We were able to detect MCPyV in 77% (n = 30) of MCC as confirmed by sequence analyses of the PCR products. Sequence analyses showed only minor nucleotide changes compared with the previously published MCC sequences. In addn., one patient revealed the amplification of two PCR products using PCR primers directed against the VP1 gene. Sequence analyses confirmed the presence of the expected 351-bp PCR product and in addn. a second PCR product of 261 bp contg. a unique 90-bp deletion in the VP1 gene, which will lead to a predicted loss of 28 amino acids. The unique 90-bp deletion within the VP1 gene possibly is a result of incomplete viral integration of MCPyV in the MCC. The presence of MCPyV in the majority of MCC tissue specimens in our study strongly underlines a possible role for MCPyV as an etiol. agent in the carcinogenesis of MCC. [Cancer Res 2008;68(13):5009-13].
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  101. 101
    Garneski, K. M.; Warcola, A. H.; Feng, Q.; Kiviat, N. B.; Leonard, J. H.; Nghiem, P. Merkel Cell Polyomavirus Is More Frequently Present in North American than Australian Merkel Cell Carcinoma Tumors. J. Invest. Dermatol. 2009, 129 (1), 246– 248,  DOI: 10.1038/jid.2008.229
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    101
    Merkel Cell Polyomavirus Is More Frequently Present in North American than Australian Merkel Cell Carcinoma Tumors
    Garneski, Kelly M.; Warcola, Ashley H.; Feng, Qinghua; Kiviat, Nancy B.; Leonard, J. Helen; Nghiem, Paul
    Journal of Investigative Dermatology (2009), 129 (1), 246-248CODEN: JIDEAE; ISSN:0022-202X. (Nature Publishing Group)
    The authors used quant. real-time PCR to detect the presence or absence of MCPyV DNA in 37 MCC tumor specimens originating from 37 patients in North America and Australia. It was found that 16 of 37 MCC tumor tissues were pos. for MCPyV DNA (43 %). Interestingly, the proportion of tumors pos. for MCPyV was much higher in tumors originating from North America than those originating from Australia. These data further present the interesting observation that North American MCC tumors are more frequently MCPyV pos. than Australian MCC tumors.
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  102. 102
    Busam, K. J.; Jungbluth, A. A.; Rekthman, N.; Coit, D.; Pulitzer, M.; Bini, J.; Arora, R.; Hanson, N. C.; Tassello, J. A.; Frosina, D.; Moore, P.; Chang, Y. Merkel Cell Polyomavirus Expression in Merkel Cell Carcinomas and Its Absence in Combined Tumors and Pulmonary Neuroendocrine Carcinomas. Am. J. Surg. Pathol. 2009, 33 (9), 1378– 1385,  DOI: 10.1097/PAS.0b013e3181aa30a5
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    102
    Merkel cell polyomavirus expression in merkel cell carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas
    Busam Klaus J; Jungbluth Achim A; Rekthman Natasha; Coit Daniel; Pulitzer Melissa; Bini Jason; Arora Reety; Hanson Nicole C; Tassello Jodie A; Frosina Denise; Moore Patrick; Chang Yuan
    The American journal of surgical pathology (2009), 33 (9), 1378-85 ISSN:.
    Merkel cell carcinoma (MCC) is the eponym for primary cutaneous neuroendocrine carcinoma. Recently, a new polyoma virus has been identified that is clonally integrated in the genome of the majority of MCCs, with truncating mutations in the viral large T antigen gene. We examined the presence of Merkel cell polyomavirus (MCV) in a set of 17 frozen tumor samples by quantitative polymerase chain reaction; 15 of them (88%) were positive. Sections from corresponding archival material were analyzed by immunohistochemistry (IHC) with the novel monoclonal antibody CM2B4, generated against a predicted antigenic epitope on the MCV T antigen, and tested for the expression of cytokeratin 20 (CK20). Sufficient archival material for IHC was available in only 15 of the 17 cases whose frozen tissue samples had been studied by polymerase chain reaction. Of the 15 tumors analyzed immunohistochemically, 10 (67%) showed positive labeling with CM2B4, 14 (93%) expressed CK20. A tissue microarray of 36 MCCs, 7 combined squamous and neuroendocrine carcinomas of the skin, and 26 pulmonary neuroendocrine carcinomas were also examined by IHC. Of the 36 MCCs assembled on a microarray, 32 (89%) tumors expressed CK20, and 27 (75%) were immunoreactive with CM2B4. The skin tumors with a combined squamous and neuroendocrine phenotype and all pulmonary neuroendocrine carcinomas failed to react with CM2B4. Our study shows that CM2B4 is a useful reagent for the diagnosis of MCC. It labels the majority of MCCs, but fails to react with pulmonary neuroendocrine carcinomas. We also found that neuroendocrine carcinomas of the skin arising in association with a squamous cell carcinoma seem to be independent of MCV.
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  103. 103
    Kwun, H. J.; Guastafierro, A.; Shuda, M.; Meinke, G.; Bohm, A.; Moore, P. S.; Chang, Y. The Minimum Replication Origin of Merkel Cell Polyomavirus Has a Unique Large T-Antigen Loading Architecture and Requires Small T-Antigen Expression for Optimal Replication. J. Virol. 2009, 83 (23), 12118– 12128,  DOI: 10.1128/JVI.01336-09
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    103
    The minimum replication origin of Merkel cell polyomavirus has a unique large T-antigen loading architecture and requires small T-antigen expression for optimal replication
    Kwun, Hyun Jin; Guastafierro, Anna; Shuda, Masahiro; Meinke, Gretchen; Bohm, Andrew; Moore, Patrick S.; Chang, Yuan
    Journal of Virology (2009), 83 (23), 12118-12128CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
    Merkel cell polyomavirus (MCV) is a recently discovered human polyomavirus causing the majority of human Merkel cell carcinomas. We mapped a 71-bp minimal MCV replication core origin sufficient for initiating eukaryotic DNA replication in the presence of wild-type MCV large T protein (LT). The origin includes a poly(T)-rich tract and eight variably oriented, GAGGC-like pentanucleotide sequences (PS) that serve as LT recognition sites. Mutation anal. shows that only four of the eight PS are required for origin replication. A single point mutation in one origin PS from a naturally occurring, tumor-derived virus reduces LT assembly on the origin and eliminates viral DNA replication. Tumor-derived LT having mutations truncating either the origin-binding domain or the helicase domain also prevent LT-origin assembly. Optimal MCV replication requires coexpression of MCV small T protein (sT), together with LT. An intact DnaJ domain on the LT is required for replication but is dispensable on the sT. In contrast, PP2A targeting by sT is required for enhanced replication. The MCV origin provides a novel model for eukaryotic replication from a defined DNA element and illustrates the selective pressure within tumors to abrogate independent MCV replication.
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  104. 104
    Diaz, J.; Wang, X.; Tsang, S. H.; Jiao, J.; You, J. Phosphorylation of Large T Antigen Regulates Merkel Cell Polyomavirus Replication. Cancers (Basel). 2014, 6 (3), 1464,  DOI: 10.3390/cancers6031464
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    104
    Phosphorylation of large T antigen regulates merkel cell polyomavirus replication
    Diaz Jason; Wang Xin; Tsang Sabrina H; You Jianxin; Jiao Jing
    Cancers (2014), 6 (3), 1464-86 ISSN:2072-6694.
    Merkel Cell Polyomavirus (MCPyV) was recently discovered as a novel human polyomavirus that is associated with ~80% of Merkel Cell Carcinomas. The Large Tumor antigen (LT) is an early viral protein which has a variety of functions, including manipulation of the cell cycle and initiating viral DNA replication. Phosphorylation plays a critical regulatory role for polyomavirus LT proteins, but no investigation of MCPyV LT phosphorylation has been performed to date. In this report mass spectrometry analysis reveals three unique phosphorylation sites: T271, T297 and T299. In vivo replication assays confirm that phosphorylation of T271 does not play a role in viral replication, while modification at T297 and T299 have dramatic and opposing effects on LT's ability to initiate replication from the viral origin. We test these mutants for their ability to bind, unwind, and act as a functional helicase at the viral origin. These studies provide a framework for understanding how phosphorylation of LT may dynamically regulate viral replication. Although the natural host cell of MCPyV has not yet been established, this work provides a foundation for understanding how LT activity is regulated and provides tools for better exploring this regulation in both natural host cells and Merkel cells.
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  105. 105
    Houben, R.; Shuda, M.; Weinkam, R.; Schrama, D.; Feng, H.; Chang, Y.; Moore, P. S.; Becker, J. C. Merkel Cell Polyomavirus-Infected Merkel Cell Carcinoma Cells Require Expression of Viral T Antigens. J. Virol. 2010, 84 (14), 7064– 7072,  DOI: 10.1128/JVI.02400-09
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    105
    Merkel cell polyomavirus-infected Merkel cell carcinoma cells require expression of viral T antigens
    Houben, Roland; Shuda, Masahiro; Weinkam, Rita; Schrama, David; Feng, Huichen; Chang, Yuan; Moore, Patrick S.; Becker, Juergen C.
    Journal of Virology (2010), 84 (14), 7064-7072CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
    Merkel cell carcinoma (MCC) is the most aggressive skin cancer. Recently, it was demonstrated that human Merkel cell polyomavirus (MCV) is clonally integrated in ∼80% of MCC tumors. However, direct evidence for whether oncogenic viral proteins are needed for the maintenance of MCC cells is still missing. To address this question, we knocked down MCV T-antigen (TA) expression in MCV-pos. MCC cell lines using three different short hairpin RNA (shRNA)-expressing vectors targeting exon 1 of the TAs. The MCC cell lines used include three newly generated MCV-infected cell lines and one MCV-neg. cell line from MCC tumors. Notably, all MCV-pos. MCC cell lines underwent growth arrest and/or cell death upon TA knockdown, whereas the proliferation of MCV-neg. cell lines remained unaffected. Despite an increase in the no. of annexin V-pos., 7-amino-actinomycin D (7-AAD)-neg. cells upon TA knockdown, activation of caspases or changes in the expression and phosphorylation of Bcl-2 family members were not consistently detected after TA suppression. Our study provides the first direct exptl. evidence that TA expression is necessary for the maintenance of MCV-pos. MCC and that MCV is the infectious cause of MCV-pos. MCC.
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  106. 106
    Houben, R.; Adam, C.; Baeurle, A.; Hesbacher, S.; Grimm, J.; Angermeyer, S.; Henzel, K.; Hauser, S.; Elling, R.; Bröcker, E. B.; Gaubatz, S.; Becker, J. C.; Schrama, D. An Intact Retinoblastoma Protein-Binding Site in Merkel Cell Polyomavirus Large T Antigen Is Required for Promoting Growth of Merkel Cell Carcinoma Cells. Int. J. cancer 2012, 130 (4), 847– 856,  DOI: 10.1002/ijc.26076
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    106
    An intact retinoblastoma protein-binding site in Merkel cell polyomavirus large T antigen is required for promoting growth of Merkel cell carcinoma cells
    Houben, Roland; Adam, Christian; Baeurle, Anne; Hesbacher, Sonja; Grimm, Johannes; Angermeyer, Sabrina; Henzel, Katharina; Hauser, Stefanie; Elling, Roland; Broecker, Eva-B.; Gaubatz, Stefan; Becker, Juergen C.; Schrama, David
    International Journal of Cancer (2012), 130 (4), 847-856CODEN: IJCNAW; ISSN:0020-7136. (John Wiley & Sons, Inc.)
    Merkel cell carcinoma (MCC) is a highly aggressive skin cancer that frequently harbours Merkel cell polyomavirus (MCV) DNA integrated in the genome of the tumor cells. In our study, we elaborate our recent finding that MCV-pos. MCC cell lines require the expression of the viral T antigens (TA). Indeed, in a xeno-transplantation model, we prove that TA expression is essential also in an in vivo situation, as knock down of TA leads to tumor regression. Moreover, rescuing TA short hairpin RNA (shRNA)-treated MCV-pos. MCC cells by ectopic expression of shRNA-insensitive TAs clearly demonstrates that the obsd. effect is caused by TA knockdown. Notably, introduction of a mutation in the LTA protein interfering with LTA binding to the retinoblastoma protein (RB) ablated this rescue. The importance of this interaction was further confirmed as LTA-specific knockdown leads to explicit cell growth inhibition. In summary, the presented data demonstrate that established MCV-pos. MCC tumors critically depend on TA expression, in particular the LTA and RB interaction, for sustained tumor growth. Consequently, interference with LTA/RB interaction appears as promising strategy to treat MCC.
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    Cimino, P. J.; Robirds, D. H.; Tripp, S. R.; Pfeifer, J. D.; Abel, H. J.; Duncavage, E. J. Retinoblastoma Gene Mutations Detected by Whole Exome Sequencing of Merkel Cell Carcinoma. Mod. Pathol. 2014, 27 (8), 1073– 1087,  DOI: 10.1038/modpathol.2013.235
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    107
    Retinoblastoma gene mutations detected by whole exome sequencing of Merkel cell carcinoma
    Cimino, Patrick J.; Robirds, Diane H.; Tripp, Sheryl R.; Pfeifer, John D.; Abel, Haley J.; Duncavage, Eric J.
    Modern Pathology (2014), 27 (8), 1073-1087CODEN: MODPEO; ISSN:0893-3952. (Nature Publishing Group)
    Merkel cell carcinoma is a highly aggressive cutaneous neuroendocrine tumor that has been assocd. with Merkel cell polyomavirus in up to 80% of cases. Merkel cell polyomavirus is believed to influence pathogenesis, at least in part, through expression of the large T antigen, which includes a retinoblastoma protein-binding domain. However, there appears to be significant clin. and morphol. overlap between polyomavirus-pos. and polyomavirus-neg. Merkel cell carcinoma cases. Although much of the recent focus of Merkel cell carcinoma pathogenesis has been on polyomavirus, the pathogenesis of polyomavirus-neg. cases is still poorly understood. We hypothesized that there are underlying human somatic mutations that unify Merkel cell carcinoma pathogenesis across polyomavirus status, and to investigate we performed whole exome sequencing on five polyomavirus-pos. cases and three polyomavirus-neg. cases. We found that there were no significant differences in the overall no. of single-nucleotide variations, copy no. variations, insertion/deletions, and chromosomal rearrangements when comparing polyomavirus-pos. to polyomavirus-neg. cases. However, we did find that the retinoblastoma pathway genes harbored a high no. of mutations in Merkel cell carcinoma. Furthermore, the retinoblastoma gene (RB1) was found to have nonsense truncating protein mutations in all three polyomavirus-neg. cases; no such mutations were found in the polyomavirus-pos. cases. In all eight cases, the retinoblastoma pathway dysregulation was confirmed by immunohistochem. Although polyomavirus-pos. Merkel cell carcinoma is believed to undergo retinoblastoma dysregulation through viral large T antigen expression, our findings demonstrate that somatic mutations in polyomavirus-neg. Merkel cell carcinoma lead to retinoblastoma dysregulation through an alternative pathway. This novel finding suggests that the retinoblastoma pathway dysregulation leads to an overlapping Merkel cell carcinoma phenotype and that oncogenesis occurs through either a polyomavirus-dependent (viral large T antigen expression) or polyomavirus-independent (host somatic mutation) mechanism.
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  108. 108
    Harms, P. W.; Vats, P.; Verhaegen, M. E.; Robinson, D. R.; Wu, Y. M.; Dhanasekaran, S. M.; Palanisamy, N.; Siddiqui, J.; Cao, X.; Su, F.; Wang, R.; Xiao, H.; Kunju, L. P.; Mehra, R.; Tomlins, S. A.; Fullen, D. R.; Bichakjian, C. K.; Johnson, T. M.; Dlugosz, A. A.; Chinnaiyan, A. M. The Distinctive Mutational Spectra of Polyomavirus-Negative Merkel Cell Carcinoma. Cancer Res. 2015, 75 (18), 3720– 3727,  DOI: 10.1158/0008-5472.CAN-15-0702
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    108
    The Distinctive Mutational Spectra of Polyomavirus-Negative Merkel Cell Carcinoma
    Harms, Paul William; Vats, Pankaj; Verhaegen, Monique Elise; Robinson, Dan R.; Wu, Yi-Mi; Dhanasekaran, Saravana Mohan; Palanisamy, Nallasivam; Siddiqui, Javed; Cao, Xuhong; Su, Fengyun; Wang, Rui; Xiao, Hong; Kunju, Lakshmi P.; Mehra, Rohit; Tomlins, Scott A.; Fullen, Douglas Randall; Bichakjian, Christopher Keram; Johnson, Timothy M.; Dlugosz, Andrzej Antoni; Chinnaiyan, Arul M.
    Cancer Research (2015), 75 (18), 3720-3727CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
    Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine tumor. Merkel cell polyomavirus (MCPyV) may contribute to tumorigenesis in a subset of tumors via inhibition of tumor suppressors such as retinoblastoma (RB1) by mutated viral T antigens, but the mol. pathogenesis of MCPyV-neg. MCC is largely unexplored. Through our MI-ONCOSEQ precision oncol. study, we performed integrative sequencing on two cases of MCPyV-neg. MCC, as well as a validation cohort of 14 addnl. MCC cases (n = 16). In addn. to previously identified mutations in TP53, RB1, and PIK3CA, we discovered activating mutations of oncogenes, including HRAS and loss-of-function mutations in PRUNE2 and NOTCH family genes in MCPyV-neg. MCC. MCPyV-neg. tumors also displayed high overall mutation burden (10.09 ± 2.32 mutations/Mb) and were characterized by a prominent UV-signature pattern with C > T transitions comprising 85% of mutations. In contrast, mutation burden was low in MCPyV-pos. tumors (0.40 ± 0.09 mutations/Mb) and lacked a UV signature. These findings suggest a potential ontol. dichotomy in MCC, characterized by either viral-dependent or UV-dependent tumorigenic pathways. Cancer Res; 75(18); 3720-7. ©2015 AACR.
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  109. 109
    Sahi, H.; Savola, S.; Sihto, H.; Koljonen, V.; Bohling, T.; Knuutila, S. RB1 Gene in Merkel Cell Carcinoma: Hypermethylation in All Tumors and Concurrent Heterozygous Deletions in the Polyomavirus-Negative Subgroup. APMIS 2014, 122 (12), 1157– 1166,  DOI: 10.1111/apm.12274
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    109
    RB1 gene in Merkel cell carcinoma: hypermethylation in all tumors and concurrent heterozygous deletions in the polyomavirus-negative subgroup
    Sahi, Helka; Savola, Suvi; Sihto, Harri; Koljonen, Virve; Bohling, Tom; Knuutila, Sakari
    APMIS (2014), 122 (12), 1157-1166CODEN: APMSEL; ISSN:1600-0463. (Wiley-Blackwell)
    Sequestration of the tumor suppressor retinoblastoma protein (RB) by the Merkel cell polyomavirus (MCV) is a crucial step in the pathogenesis of Merkel cell carcinoma (MCC). RB expression is frequently lost, particularly in MCV-neg. MCC tumors, through yet unknown mechanisms. We compared the genomic copy no. changes of 13 MCV-pos. and 13 -neg. MCC tumors by array comparative genomic hybridization. The anal. revealed increased genomic instability, amplification of 1p34.3-1p34.2, and losses of 11p in the absence of MCV infection. Deletions of the RB1 locus were also detected at high rates in MCV-neg. tumors. None of the tumors with heterozygous RB1 losses expressed RB in immunohistochem. RB1 promoter hypermethylation was studied with a methylation-specific multiplex ligation-dependent probe amplification technique. The RB1 promoter was methylated in all tumor specimens at CpG islands located close to the ATG start codon, albeit at low levels. The pattern of hypermethylation was similar in all MCC samples, despite RB expression, survival or MCV status. In conclusion, the frequent heterozygous losses of the RB1 locus could partly explain the decreased RB expression in MCV-neg. MCC tumors, although the effects of RB1 mutations, coinciding promoter hypermethylation and, for example, miRNA regulation, cannot be excluded.
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  110. 110
    Starrett, G. J.; Marcelus, C.; Cantalupo, P. G.; Katz, J. P.; Cheng, J.; Akagi, K.; Thakuria, M.; Rabinowits, G.; Wang, L. C.; Symer, D. E.; Pipas, J. M.; Harris, R. S.; DeCaprio, J. A. Merkel Cell Polyomavirus Exhibits Dominant Control of the Tumor Genome and Transcriptome in Virus-Associated Merkel Cell Carcinoma. MBio 2017, 8 (1), e02079,  DOI: 10.1128/mBio.02079-16
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    110
    Merkel cell polyomavirus exhibits dominant control of the tumor genome and transcriptome in virus-associated merkel cell carcinoma
    Starrett, Gabriel J.; Marcelus, Christina; Cantalupo, Paul G.; Katz, Joshua P.; Cheng, Jingwei; Akagi, Keiko; Thakuria, Manisha; Rabinowits, Guilherme; Wang, Linda C.; Symer, David E.; Pipas, James M.; Harris, Reuben S.; DeCaprio, James A.
    mBio (2017), 8 (1), e02079-16/1-e02079-16/14CODEN: MBIOCL; ISSN:2150-7511. (American Society for Microbiology)
    Merkel cell polyomavirus is the primary etiol. agent of the aggressive skin cancer Merkel cell carcinoma (MCC). Recent studies have revealed that UV radiation is the primary mechanism for somatic mutagenesis in nonviral forms of MCC. Here, we analyze the whole transcriptomes and genomes of primary MCC tumors. Our study reveals that virus-assocd. tumors have minimally altered genomes compared to non-virus-assocd. tumors, which are dominated by UV-mediated mutations. Although virus-assocd. tumors contain relatively small mutation burdens, they exhibit a distinct mutation signature with observable transcriptionally biased kataegic events. In addn., viral integration sites overlap focal genome amplifications in virus-assocd. tumors, suggesting a potential mechanism for these events. Collectively, our studies indicate that Merkel cell polyomavirus is capable of hijacking cellular processes and driving tumorigenesis to the same severity as tens of thousands of somatic genome alterations.
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  111. 111
    Borchert, S.; Czech-Sioli, M.; Neumann, F.; Schmidt, C.; Wimmer, P.; Dobner, T.; Grundhoff, A.; Fischer, N. High-Affinity Rb Binding, P53 Inhibition, Subcellular Localization, and Transformation by Wild-Type or Tumor-Derived Shortened Merkel Cell Polyomavirus Large T Antigens. J. Virol. 2014, 88 (6), 3144– 3160,  DOI: 10.1128/JVI.02916-13
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    111
    High-affinity Rb binding, p53 inhibition, subcellular localization and transformation by wild-type or tumor-derived shortened Merkel cell polyomavirus large T antigens
    Borchert, Sophie; Czech-Sioli, Manja; Neumann, Friederike; Schmidt, Claudia; Wimmer, Peter; Dobner, Thomas; Grundhoff, Adam; Fischer, Nicole
    Journal of Virology (2014), 88 (6), 3144-3160, 18 pp.CODEN: JOVIAM; ISSN:1098-5514. (American Society for Microbiology)
    Interference with tumor suppressor pathways by polyomavirus-encoded tumor antigens (T-Ags) can result in transformation. Consequently, it is thought that T-Ags encoded by Merkel cell polyomavirus (MCPyV), a virus integrated in ∼90% of all Merkel cell carcinoma (MCC) cases, are major contributors to tumorigenesis. The MCPyV large T-Ag (LT-Ag) has preserved the key functional domains present in all family members but has also acquired unique regions that flank the LxCxE motif. As these regions may mediate unique functions or may modulate those shared with T-Ags of other polyomaviruses, functional studies of MCPyV T-Ags are required. Here, we have performed a comparative study of full-length or MCC-derived truncated LT-Ags with regard to their biochem. characteristics, their ability to bind to retinoblastoma (Rb) and p53 proteins and their transforming potential. We provide evidence that full-length MCPyV LT-Ag may not directly bind to p53 but nevertheless can significantly reduce p53-dependent transcription in reporter assays. Although early region expression constructs harboring either full-length or MCC-derived truncated LT-Ag genes can transform primary baby rat kidney cells, truncated LT-Ags do not bind to p53 or reduce p53-dependent transcription. Interestingly, shortened LT-Ags exhibit a very high binding affinity for Rb, as shown by coimmunopptn. and in vitro binding studies. Addnl., we show that truncated MCPyV LT-Ag proteins are expressed at higher levels than those for the wild-type protein and are able to partially relocalize Rb to the cytoplasm, indicating that truncated LT proteins may have gained addnl. features that distinguish them from the full-length protein.
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  112. 112
    Cheng, J.; Rozenblatt-Rosen, O.; Paulson, K. G.; Nghiem, P.; DeCaprio, J. A. Merkel Cell Polyomavirus Large T Antigen Has Growth-Promoting and Inhibitory Activities. J. Virol. 2013, 87 (11), 6118,  DOI: 10.1128/JVI.00385-13
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    112
    Merkel cell polyomavirus large T antigen has growth-promoting and inhibitory activities
    Cheng, Jingwei; Rozenblatt-Rosen, Orit; Paulson, Kelly G.; Nghiem, Paul; DeCaprio, James A.
    Journal of Virology (2013), 87 (11), 6118-6126CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
    Merkel cell carcinoma (MCC) is a rare and aggressive form of skin cancer. In at least 80% of all MCC, Merkel cell polyomavirus (MCPyV) DNA has undergone clonal integration into the host cell genome, and most tumors express the MCPyV large and small T antigens. In all cases of MCC reported to date, the integrated MCPyV genome has undergone mutations in the large T antigen. These mutations result in expression of a truncated large T antigen that retains the Rb binding or LXCXE motif but deletes the DNA binding and helicase domains. However, the transforming functions of full-length and truncated MCPyV large T antigen are unknown. We compared the transforming activities of full-length, truncated, and alternatively spliced 57kT forms of MCPyV large T antigen. MCPyV large T antigen could bind to Rb but was unable to bind to p53. Furthermore, MCPyV-truncated large T antigen was more effective than full-length and 57kT large T antigen in promoting the growth of human and mouse fibroblasts. In contrast, expression of the MCPyV large T antigen C-terminal 100 residues could inhibit the growth of several different cell types. These data imply that the deletion of the C terminus of MCPyV large T antigen found in MCC serves not only to disrupt viral replication but also results in the loss of a distinct growth-inhibitory function intrinsic to this region.
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  113. 113
    Li, J.; Wang, X.; Diaz, J.; Tsang, S. H.; Buck, C. B.; You, J. Merkel Cell Polyomavirus Large T Antigen Disrupts Host Genomic Integrity and Inhibits Cellular Proliferation. J. Virol. 2013, 87 (16), 9173,  DOI: 10.1128/JVI.01216-13
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    113
    Merkel cell polyomavirus large T antigen disrupts host genomic integrity and inhibits cellular proliferation
    Li, Jing; Wang, Xin; Diaz, Jason; Tsang, Sabrina H.; Buck, Christopher B.; You, Jianxin
    Journal of Virology (2013), 87 (16), 9173-9188CODEN: JOVIAM; ISSN:1098-5514. (American Society for Microbiology)
    Clonal integration of Merkel cell polyomavirus (MCV) DNA into the host genome has been obsd. in at least 80% of Merkel cell carcinoma (MCC). The integrated viral genome typically carries mutations that truncate the C-terminal DNA binding and helicase domains of the MCV large T antigen (LT), suggesting a selective pressure to remove this MCV LT region during tumor development. In this study, we show that MCV infection leads to the activation of host DNA damage responses (DDR). This activity was mapped to the C-terminal helicase-contg. region of the MCV LT. The MCV LT-activated DNA damage kinases, in turn, led to enhanced p53 phosphorylation, upregulation of p53 downstream target genes, and cell cycle arrest. Compared to the N-terminal MCV LT fragment that is usually preserved in mutants isolated from MCC tumors, full-length MCV LT shows a decreased potential to support cellular proliferation, focus formation, and anchorage-independent cell growth. These apparently antitumorigenic effects can be reversed by a dominant-neg. p53 inhibitor. Our results demonstrate that MCV LT-induced DDR activates p53 pathway, leading to the inhibition of cellular proliferation. This study reveals a key difference between MCV LT and simian vacuolating virus 40 LT, which activates a DDR but inhibits p53 function. This study also explains, in part, why truncation mutations that remove the MCV LT C-terminal region are necessary for the oncogenic progression of MCV-assocd. cancers.
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  114. 114
    Shuda, M.; Kwun, H. J.; Feng, H.; Chang, Y.; Moore, P. S. Human Merkel Cell Polyomavirus Small T Antigen Is an Oncoprotein Targeting the 4E-BP1 Translation Regulator. J. Clin. Invest. 2011, 121 (9), 3623– 3634,  DOI: 10.1172/JCI46323
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    114
    Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator
    Shuda, Masahiro; Kwun, Hyun Jin; Feng, Huichen; Chang, Yuan; Moore, Patrick S.
    Journal of Clinical Investigation (2011), 121 (9), 3623-3634CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)
    Merkel cell polyomavirus (MCV) is the recently discovered cause of most Merkel cell carcinomas (MCCs), an aggressive form of nonmelanoma skin cancer. Although MCV is known to integrate into the tumor cell genome and to undergo mutation, the mol. mechanisms used by this virus to cause cancer are unknown. Here, we show that MCV small T (sT) antigen is expressed in most MCC tumors, where it is required for tumor cell growth. Unlike the closely related SV40 sT, MCV sT transformed rodent fibroblasts to anchorage- and contact-independent growth and promoted serum-free proliferation of human cells. These effects did not involve protein phosphatase 2A (PP2A) inhibition. MCV sT was found to act downstream in the mammalian target of rapamycin (mTOR) signaling pathway to preserve eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) hyperphosphorylation, resulting in dysregulated cap-dependent translation. MCV sT-assocd. 4E-BP1 serine 65 hyperphosphorylation was resistant to mTOR complex (mTORC1) and mTORC2 inhibitors. Steady-state phosphorylation of other downstream Akt-mTOR targets, including S6K and 4E-BP2, was also increased by MCV sT. Expression of a constitutively active 4E-BP1 that could not be phosphorylated antagonized the cell transformation activity of MCV sT. Taken together, these expts. showed that 4E-BP1 inhibition is required for MCV transformation. Thus, MCV sT is an oncoprotein, and its effects on dysregulated cap-dependent translation have clin. implications for the prevention, diagnosis, and treatment of MCV-related cancers.
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  115. 115
    Rodriguez-Viciana, P.; Collins, C.; Fried, M. Polyoma and SV40 Proteins Differentially Regulate PP2A to Activate Distinct Cellular Signaling Pathways Involved in Growth Control. Proc. Natl. Acad. Sci. U. S. A. 2006, 103 (51), 19290,  DOI: 10.1073/pnas.0609343103
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    115
    Polyoma and SV40 proteins differentially regulate PP2A to activate distinct cellular signaling pathways involved in growth control
    Rodriguez-Viciana, Pablo; Collins, Crista; Fried, Mike
    Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (51), 19290-19295CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Binding of Src family kinases to membrane-assocd. polyoma virus middle T-antigen (PyMT) can result in the phosphorylation of PyMT tyrosine 250, which serves as a docking site for the binding of Shc and subsequent activation of the Raf-MEK-ERK (MAP) kinase cascade. In a screen for PyMT variants that could not activate the ARF tumor suppressor, we isolated a cytoplasmic nontransforming mutant (MTA) that encoded a C-terminal truncated form of the PyMT protein. Surprisingly, MTA was able to strongly activate the MAP kinase pathway in the absence of Src family kinase and Shc binding. Interestingly, the polyoma small T-antigen (PyST), which shares with MTA both partial amino acid sequence homol. and cellular location, also activates the MAP kinase cascade. Activation of the MAP kinase cascade by both MTA and PyST has been demonstrated to be PP2A-dependent. Neither MTA nor PyST activate the phosphorylation of AKT. The SV40 small T-antigen, which is similar to PyST in contg. a J domain and in binding to the PP2A AC dimer, does not activate the MAP kinase cascade, but does stimulate phosphorylation of AKT in a PP2A-dependent manner. These findings highlight a novel role of PP2A in stimulating the MAP kinase cascade and indicate that the similar polyoma and SV40 small T-antigens influence PP2A to activate discrete cellular signaling pathways involved in growth control.
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  116. 116
    Kwun, H. J.; Shuda, M.; Camacho, C. J.; Gamper, A. M.; Thant, M.; Chang, Y.; Moore, P. S. Restricted Protein Phosphatase 2A Targeting by Merkel Cell Polyomavirus Small T Antigen. J. Virol. 2015, 89 (8), 4191– 4200,  DOI: 10.1128/JVI.00157-15
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    116
    Restricted protein phosphatase 2A targeting by Merkel cell polyomavirus small T antigen
    Kwun, Hyun Jin; Shuda, Masahiro; Camacho, Carlos J.; Gamper, Armin M.; Thant, Mamie; Chang, Yuan; Moore, Patrick S.
    Journal of Virology (2015), 89 (8), 4191-4200CODEN: JOVIAM; ISSN:1098-5514. (American Society for Microbiology)
    Merkel cell polyomavirus (MCV) is a newly discovered human cancer virus encoding a small T (sT) oncoprotein. We performed MCV sT FLAG-affinity purifn. followed by mass spectroscopy (MS) anal., which identified several protein phosphatases (PP), including PP2A A and C subunits and PP4C, as potential cellular interacting proteins. PP2A targeting is crit. for the transforming properties of nonhuman polyomaviruses, such as simian virus 40 (SV40), but is not required for MCV sT-induced rodent cell transformation. We compared similarities and differences in PP2A binding between MCV and SV40 sT. While SV40 sT coimmunopurified with subunits PP2A Aα and PP2A C, MCV sT coimmunopurified with PP2A Aα, PP2A Aβ, and PP2A C. Scanning alanine mutagenesis at 29 sites across the MCV sT protein revealed that PP2A-binding domains lie on the opposite mol. surface from a previously described large T stabilization domain (LSD) loop that binds E3 ligases, such as Fbw7. MCV sT-PP2A interactions can be functionally distinguished by mutagenesis from MCV sT LSD-dependent 4E-BP1 hyperphosphorylation and viral DNA replication enhancement. MCV sT has a restricted range for PP2A B subunit substitution, inhibiting only the assembly of B56α into the phosphatase holoenzyme. In contrast, SV40 sT inhibits the assembly of B55α, B56α and B56ε into PP2A. We conclude that MCV sT is required for Merkel cell carcinoma growth, but its in vitro transforming activity depends on LSD interactions rather than PP2A targeting.
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  117. 117
    Munde, P. B.; Khandekar, S. P.; Dive, A. M.; Sharma, A. Pathophysiology of Merkel Cell. J. Oral Maxillofac. Pathol. 2013, 17 (3), 408,  DOI: 10.4103/0973-029X.125208
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    117
    Pathophysiology of merkel cell
    Munde Prashant Balasaheb; Khandekar Shubhangi P; Dive Alka M; Sharma Aparna
    Journal of oral and maxillofacial pathology : JOMFP (2013), 17 (3), 408-12 ISSN:0973-029X.
    The objective of this review is to introduce Merkel cells (MCs), to provide a basic overview on the theoretical background of function, development and clinical importance of MCs. The origin of human MCs have been controversial. Some investigators believe that it is a neural crest derivate, whereas others have proposed that it is a differentiation product of the fetal epidermal keratinocytes. MCs are cells primarily localized in the epidermal basal layer of vertebrates and concentrated in touch-sensitive areas in glabrous, hairy skin and in some mucosa. In routine light microscopy, human MCs can hardly be identified. Cytokeratin 20 (CK20) is a reliable marker with highest degree of specificity. MCs can be also distinguished by electron microscopy. MC carcinoma (MCC) is an uncommon and often aggressive malignancy and found mainly in elderly patients. It occurs most frequently in the head and neck region. Diagnosis is based on typical histological presentation on hematoxylin and eosin (H and E) stained slides together with the results of immunohistochemistry. Histologically, MCC has been classified into three distinct subtypes: Trabecular, intermediate and small cell type.
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  118. 118
    zur Hausen, A.; Rennspiess, D.; Winnepenninckx, V.; Speel, E.-J.; Kurz, A. K. Early B-Cell Differentiation in Merkel Cell Carcinomas: Clues to Cellular Ancestry. Cancer Res. 2013, 73 (16), 4982– 4987,  DOI: 10.1158/0008-5472.CAN-13-0616
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    118
    Early B-Cell Differentiation in Merkel Cell Carcinomas: Clues to Cellular Ancestry
    zur Hausen, Axel; Rennspiess, Dorit; Winnepenninckx, Veronique; Speel, Ernst-Jan; Kurz, Anna Kordelia
    Cancer Research (2013), 73 (16), 4982-4987CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
    Merkel cell carcinoma (MCC) is a highly malignant neuroendocrine nonmelanoma skin cancer, which is assocd. with the Merkel cell polyoma virus (MCPyV). Recently, expression of the terminal deoxynucleotidyl transferase (TdT) and the paired box gene 5 (PAX 5) has been consistently reported in the majority of MCCs. We tested 21 MCCs for the expression of MCPyV, TdT, PAX5, IgG, IgM, IgA, kappa, and lambda by immunohistochem. and assessed IgH and Igk rearrangement in all 21 MCCs. All of the MCCs revealed specific expression of PAX5 and 72.8% of the MCCs expressed TdT. In addn., most of the MCCs revealed specific expression of one or more Ig subclasses and kappa or lambda. One MCC did reveal monoclonal IgH and Igk rearrangement next to two other MCCs showing Igk rearrangement. As coexpression of TdT and PAX5 under physiol. circumstances is restricted to pro/pre- and pre-B cells we propose, on the basis of our results, that the cell of origin of MCCs is a pro/pre- or pre-B cell rather than the postmitotic Merkel cells. MCPyV infection and transformation of pro-/pre-B cells are likely to induce the expression of simple cytokeratins as has been shown for SV40 in other nonepithelial cells. This model of cellular ancestry of MCCs might impact therapy and possibly helps to understand why approx. 20% of MCCs are MCPyV-neg.
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  119. 119
    Calder, K. B.; Smoller, B. R. New Insights into Merkel Cell Carcinoma. Adv. Anat. Pathol. 2010, 17 (3), 155– 161,  DOI: 10.1097/PAP.0b013e3181d97836
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    119
    New insights into merkel cell carcinoma
    Calder Kenneth B; Smoller Bruce R
    Advances in anatomic pathology (2010), 17 (3), 155-61 ISSN:.
    Merkel cell carcinoma (MCC) is a rare aggressive cutaneous malignancy of the elderly and immunocompromised populations. The clinical presentation of MCC is nonspecific, with the majority of cases presenting as localized skin involvement. Histologically and immunophenotypically, MCC is defined by both neuroendocrine and epithelial differentiation. Recently, the Merkel cell polyomavirus has been implicated in the pathogenesis of MCC. In addition, there have been numerous studies evaluating the histologic and immunohistochemical characteristics of MCC as they relate to diagnosis and prognosis. The purpose of this paper is to review the most salient and clinically relevant updates in the pathogenesis and histologic features of MCC. Specific attention is given to the clinical and histologic predictors of prognosis, staging, and the controversies concerning sentinel lymph node biopsy and therapy.
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  120. 120
    Fan, K.; Gravemeyer, J.; Ritter, C.; Rasheed, K.; Gambichler, T.; Moens, U.; Shuda, M.; Schrama, D.; Becker, J. C. MCPyV Large T Antigen-Induced Atonal Homolog 1 Is a Lineage-Dependency Oncogene in Merkel Cell Carcinoma. J. Invest. Dermatol. 2020, 140 (1), 56– 65, e3  DOI: 10.1016/j.jid.2019.06.135
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    120
    MCPyV Large T Antigen-Induced Atonal Homolog 1 Is a Lineage-Dependency Oncogene in Merkel Cell Carcinoma
    Fan, Kaiji; Gravemeyer, Jan; Ritter, Cathrin; Rasheed, Kashif; Gambichler, Thilo; Moens, Ugo; Shuda, Masahiro; Schrama, David; Becker, Juergen C.
    Journal of Investigative Dermatology (2020), 140 (1), 56-65.e3CODEN: JIDEAE; ISSN:0022-202X. (Elsevier Inc.)
    Despite the fact that the transcription factor ATOH1 is a master regulator of Merkel cell development, its role in Merkel cell carcinoma (MCC) carcinogenesis remains controversial. Here, we provide several lines of evidence that ATOH1 is a lineage-dependent oncogene in MCC. Luciferase assays revealed binding of ATOH1 and subsequent activation to the promoter of miR-375, which is one of the most abundant microRNAs in MCCs. Overexpression of ATOH1 in variant MCC cell lines and fibroblasts induced miR-375 expression, whereas ATOH1 knockdown in classical MCC cell lines reduced miR-375 expression. Moreover, ATOH1 overexpression in these cells changed their growth characteristics from adherent to suspension and/orspheroidal growth, i.e., resembling the neuroendocrine growth pattern of classical MCC cell lines. Notably, ectopic expression of different Merkel cell polyomavirus (MCPyV)-derived truncated large T antigens induced ATOH1 expression in fibroblasts, which was paralleled by miR-375 expression and similar morphol. changes. In summary, MCPyV-assocd. carcinogenesis is likely to induce the characteristic neuroendocrine features of MCC via induction of ATOH1; thus, ATOH1 can be regarded as a lineage-dependent oncogene in MCC.
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  121. 121
    Liu, W.; You, J. Molecular Mechanisms of Merkel Cell Polyomavirus Transformation and Replication. Annu. Rev. Virol. 2020, 7 (1), 289,  DOI: 10.1146/annurev-virology-011720-121757
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    121
    Molecular Mechanisms of Merkel Cell Polyomavirus Transformation and Replication
    Liu, Wei; You, Jianxin
    Annual Review of Virology (2020), 7 (), 289-307CODEN: ARVNBS; ISSN:2327-0578. (Annual Reviews)
    Viral infection underlies a significant share of the global cancer burden. Merkel cell polyomavirus (MCPyV) is the newest member of the human oncogenic virus family. Its discovery over a decade ago marked the beginning of an exciting era in human tumor virol. Since then, significant evidences have emerged to support the etiol. role of MCPyV in Merkel cell carcinoma (MCC), an extremely lethal form of skin cancer. MCPyV infection is widespread in the general population. MCC diagnoses have tripled over the past 20 years, but effective treatments are currently lacking. In this review, we highlight recent discoveries that have shaped our understanding of MCPyV oncogenic mechanism and host cellular tropism, as well as the mol. events occurring in the viral infectious life cycle. These insights will guide future efforts in developing novel virus-targeted therapeutic strategies for treating the devastating human cancers assocd. with this new tumorigenic virus.
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    Global epidemiology of hepatitis C virus infection
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    Hepatitis C virus (HCV) is a major cause of liver disease worldwide and a potential cause of substantial morbidity and mortality in the future. The complexity and uncertainty related to the geographic distribution of HCV infection and chronic hepatitis C, determination of its associated risk factors, and evaluation of cofactors that accelerate its progression, underscore the difficulties in global prevention and control of HCV. Because there is no vaccine and no post-exposure prophylaxis for HCV, the focus of primary prevention efforts should be safer blood supply in the developing world, safe injection practices in health care and other settings, and decreasing the number of people who initiate injection drug use.
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    A review. Chronic infection with hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC). Novel treatments with direct-acting antivirals achieve high rates of sustained virol. response; however, the HCC risk remains elevated in cured patients, esp. those with advanced liver disease. Long-term HCV infection causes a persistent and accumulating damage of the liver due to a combination of direct and indirect pro-oncogenic mechanisms. This review describes the processes involved in virus-induced disease progression by viral proteins, derailed signaling, immunity, and persistent epigenetic deregulation, which may be instrumental to develop urgently needed prognostic biomarkers and as targets for novel chemopreventive therapies.
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    Overwhelming lines of epidemiological evidence have indicated that chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) is a major risk for the development of hepatocellular carcinoma (HCC). In the pathogenesis of HCC associated with HBV or HCV, it remains controversial whether these hepatitis viruses play a direct role or merely an indirect role. By virtue of transgenic mice established by us, it has become evident that the product of the HBV X gene (HBx protein) and the core protein of HCV have an oncogenic potential, although the pathways through which these two viral proteins operate may differ. The findings in our studies indicate that HBV and HCV are directly involved in hepatocarcinogenesis, albeit other factors such as continued cell death and regeneration associated with chronic hepatitis may play a role as well. Combined, our results suggest that there might be a mechanism in the development of HCC in persistent infection with hepatitis viruses that is distinct from that in other cancers. Similarly to the pathogenesis of other malignancies represented by colorectal cancer, the accumulation of a set of genetic aberrations may also be necessary for a multistage development of HCC. However, HBx protein and HCV core protein, to which an oncogenic potential is attributed, may allow some of the multiple stages skipped in hepatocarcinogenesis. Unlike for the other cancers, therefore, infection with HBV or HCV may be capable of inducing HCC in the absence of a complete set of genetic aberrations. Such a scenario would explain an unusually high incidence and multicentric nature of HCC developing in chronic hepatitis B or C.
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    Hepatitis C virus (HCV) is a major cause of chronic liver disease, with an estd. 170 million people infected worldwide. Low yields, poor stability, and inefficient binding to conventional EM grids have posed significant challenges to the purifn. and structural anal. of HCV. In this report, we generated an infectious HCV genome with an affinity tag fused to the E2 envelope glycoprotein. Using affinity grids, previously described to isolate proteins and macromol. complexes for single-particle EM, we were able to purify enveloped particles directly from cell culture media. This approach allowed for rapid in situ purifn. of virions and increased particle d. that were instrumental for cryo-EM and cryoelectron tomog. (cryo-ET). Moreover, it enabled ultrastructural anal. of virions produced by primary human hepatocytes. HCV appears to be the most structurally irregular member of the Flaviviridae family. Particles are spherical, with spike-like projections, and heterogeneous in size ranging from 40 to 100 nm in diam. Exosomes, although isolated from unfractionated culture media, were absent in highly infectious, purified virus prepns. Cryo-ET studies provided low-resoln. 3D structural information of highly infectious virions. In addn. to apolipoprotein (apo)E, HCV particles also incorporate apoB and apoA-I. In general, host apolipoproteins were more readily accessible to antibody labeling than HCV glycoproteins, suggesting either lower abundance or masking by host proteins.
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    Echeverría, N.; Moratorio, G.; Cristina, J.; Moreno, P. Hepatitis C Virus Genetic Variability and Evolution. World J. Hepatol. 2015, 7 (6), 831,  DOI: 10.4254/wjh.v7.i6.831
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    Hepatitis C virus (HCV) has infected over 170 million people worldwide and creates a huge disease burden due to chronic, progressive liver disease. HCV is a single-stranded, positive sense, RNA virus, member of the Flaviviridae family. The high error rate of RNA-dependent RNA polymerase and the pressure exerted by the host immune system, has driven the evolution of HCV into 7 different genotypes and more than 67 subtypes. HCV evolves by means of different mechanisms of genetic variation. On the one hand, its high mutation rates generate the production of a large number of different but closely related viral variants during infection, usually referred to as a quasispecies. The great quasispecies variability of HCV has also therapeutic implications since the continuous generation and selection of resistant or fitter variants within the quasispecies spectrum might allow viruses to escape control by antiviral drugs. On the other hand HCV exploits recombination to ensure its survival. This enormous viral diversity together with some host factors has made it difficult to control viral dispersal. Current treatment options involve pegylated interferon-α and ribavirin as dual therapy or in combination with a direct-acting antiviral drug, depending on the country. Despite all the efforts put into antiviral therapy studies, eradication of the virus or the development of a preventive vaccine has been unsuccessful so far. This review focuses on current available data reported to date on the genetic mechanisms driving the molecular evolution of HCV populations and its relation with the antiviral therapies designed to control HCV infection.
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    A review. This document aims to provide clinicians with evidence-based approaches to the prevention, diagnosis, and management of hepatitis C virus (HCV) infection. Current data on the recommended treatments of patients with chronic HCV infection are included. The sequential steps recommended for managing and treating persons chronically infected with hepatitis C for whom treatment is considered clearly appropriate are summarized.
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    Zhu, Y. Z.; Qian, X. J.; Zhao, P.; Qi, Z. T. How Hepatitis C Virus Invades Hepatocytes: The Mystery of Viral Entry. World J. Gastroenterol. 2014, 20 (13), 3457– 3467,  DOI: 10.3748/wjg.v20.i13.3457
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    How hepatitis C virus invades hepatocytes: the mystery of viral entry
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    A review. Hepatitis C virus (HCV) infection is a global health problem, with an estd. 170 million people being chronically infected. HCV cell entry is a complex multi-step process, involving several cellular factors that trigger virus uptake into the hepatocytes. The high- d. lipoprotein receptor scavenger receptor class B type I, tetraspanin CD81, tight junction protein claudin-1, and occludin are the main receptors that mediate the initial step of HCV infection. In addn., the virus uses cell receptor tyrosine kinases as entry regulators, such as epidermal growth factor receptor and ephrin receptor A2. This review summarizes the current understanding about how cell surface mols. are involved in HCV attachment, internalization, and membrane fusion, and how host cell kinases regulate virus entry. The advances of the potential antiviral agents targeting this process are introduced.
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    Structures of hepatitis C virus nonstructural proteins required for replicase assembly and function
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    A review. Approx. 3% of the world population is infected with hepatitis C virus (HCV), causing a serious public health burden. Like other pos.-strand RNA viruses, HCV assembles replicase complexes in assocn. with cellular membranes and produces progeny RNA genomes through neg.-strand intermediates. The viral proteins required for RNA replication are nonstructural (NS) proteins NS3 to NS5B. Owing to many obstacles and limitations in structural characterization of proteins and complexes with multiple transmembrane segments, attempts to understand the assembly and action of the HCV replicase complex have been challenging. Nevertheless, great progress has been made in obtaining structural information for several replicase components, providing insights into some aspects of the viral genome replication machinery.
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    Pawlotsky, J. M. Hepatitis C Virus: Standard-of-Care Treatment. Adv. Pharmacol. 2013, 67, 169– 215,  DOI: 10.1016/B978-0-12-405880-4.00005-6
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    Hepatitis C virus: standard-of-care treatment
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    A review. Hepatitis C virus (HCV) infection is curable by therapy. The antiviral treatment of chronic hepatitis C has been based for decades on the use of interferon (IFN)-α, combined with ribavirin. More recently, new therapeutic approaches that target essential components of the HCV life cycle have been developed, including direct-acting antiviral (DAA) and host-targeted agents (HTA). A new std.-of-care treatment has been approved in 2011 for patients infected with HCV genotype 1, based on a triple combination of pegylated IFN-α, ribavirin, and either telaprevir or boceprevir, two inhibitors of the HCV protease. New triple and quadruple combination therapies including pegylated IFN-α, ribavirin, and one or two DAAs/HTAs, resp., are currently being evaluated in Phase II and III clin. trials. In addn., various options for all-oral, IFN-free regimens are currently being evaluated. This chapter describes the characteristics of the different drugs used in the treatment of chronic hepatitis C and those currently in development and provides an overview of the current and future std.-of-care treatments of chronic hepatitis C.
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    Bartenschlager, R.; Lohmann, V.; Penin, F. The Molecular and Structural Basis of Advanced Antiviral Therapy for Hepatitis C Virus Infection. Nat. Rev. Microbiol. 2013, 11 (7), 482– 496,  DOI: 10.1038/nrmicro3046
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    The molecular and structural basis of advanced antiviral therapy for hepatitis C virus infection
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    A review. The availability of the first mol. clone of the hepatitis C virus (HCV) genome allowed the identification and biochem. characterization of two viral enzymes that are targets for antiviral therapy: the protease NS3-4A and the RNA-dependent RNA polymerase NS5B. With the advent of cell culture systems that can recapitulate either the intracellular steps of the viral replication cycle or the complete cycle, addnl. drug targets have been identified, most notably the phosphoprotein NS5A, but also host cell factors that promote viral replication, such as cyclophilin A. Here, we review insights into the structures of these proteins and the mechanisms by which they contribute to the HCV replication cycle, and discuss how these insights have facilitated the development of new, directly acting antiviral compds. that have started to enter the clinic.
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    Pawlotsky, J. M. What Are the Pros and Cons of the Use of Host-Targeted Agents against Hepatitis C?. Antiviral Res. 2014, 105 (1), 22,  DOI: 10.1016/j.antiviral.2014.02.008
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    Antiviral Research (2014), 105 (), 22-25CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
    A review. Hepatitis C virus (HCV) therapy is living a revolution. Host-targeted agents (HTAs) block HCV prodn. by interacting with host cell components. Because they target conserved host proteins, not variable viral proteins, HTAs have the potential for pangenotypic antiviral activity and a high barrier to resistance. Only two HTAs have reached clin. development, including specific inhibitors of cyclophilin A peptidyl-prolyl cis/trans isomerase activity and antagonists of microRNA-122. Cyclophilin inhibitors have proven to be relatively well tolerated and can be confidently used as backbones of all-oral, interferon-free regimens. In addn., HTAs such as cyclophilin inhibitors offer opportunities for "panviral" approaches when they target mechanisms common to viruses of the same or different families. This article forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication.".
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    Scheel, T. K. H.; Rice, C. M. Understanding the Hepatitis C Virus Life Cycle Paves the Way for Highly Effective Therapies. Nat. Med. 2013, 19 (7), 837– 849,  DOI: 10.1038/nm.3248
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    Understanding the hepatitis C virus life cycle paves the way for highly effective therapies
    Scheel, Troels K. H.; Rice, Charles M.
    Nature Medicine (New York, NY, United States) (2013), 19 (7), 837-849CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
    A review. More than two decades of intense research has provided a detailed understanding of hepatitis C virus (HCV), which chronically infects 2% of the world's population. This effort has paved the way for the development of antiviral compds. to spare patients from life-threatening liver disease. An exciting new era in HCV therapy dawned with the recent approval of two viral protease inhibitors, used in combination with pegylated interferon-α and ribavirin; however, this is just the beginning. Multiple classes of antivirals with distinct targets promise highly efficient combinations, and interferon-free regimens with short treatment duration and fewer side effects are the future of HCV therapy. Ongoing and future trials will det. the best antiviral combinations and whether the current seemingly rich pipeline is sufficient for successful treatment of all patients in the face of major challenges, such as HCV diversity, viral resistance, the influence of host genetics, advanced liver disease and other co-morbidities.
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    A review. A hallmark of the hepatitis C virus (HCV) replication cycle is its tight link with host cell lipid synthesis. This is best illustrated by the peculiar pathway used for the assembly of infectious HCV particles. Research in the past few years has shown that formation of HC-virions is closely connected to lipid droplets that could serve as an assembly platform. Moreover, HCV particle prodn. appears to be strictly linked to very-low-d. lipoproteins. Here, the authors focus on new insights into the mol. aspects of the architecture and assembly of this unique type of virus particle.
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    Annual Review of Biophysics (2008), 37 (), 353-373CODEN: ARBNCV ISSN:. (Annual Reviews Inc.)
    A review. High-resoln. X-ray crystal structures detd. in the past six years dramatically influence our view of ligand-induced activation of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. Ligand binding to the extracellular region of EGFR promotes a major domain reorganization, plus local conformational changes, that are required to generate an entirely receptor-mediated dimer. In this activated complex the intracellular kinase domains assoc. to form an asym. dimer that supports the allosteric activation of one kinase. These models are discussed with emphasis on recent studies that add details or bolster the generality of this view of activation of this family of receptors. The EGFR family is implicated in several disease states, perhaps most notably in cancers. Activating tumor mutations have been identified in the intracellular and extracellular regions of EGFR. The impact of these tumor mutations on the understanding of EGFR activation and of its inhibition is discussed.
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    Nature Reviews Molecular Cell Biology (2006), 7 (7), 505-516CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)
    A review. Signaling through the ErbB/HER receptors is intricately involved in human cancer and already serves as a target for several cancer drugs. Because of its inherent complexity, it is useful to envision ErbB signaling as a bow-tie-configured, evolvable network, which shares modularity, redundancy, and control circuits with robust biol. and engineered systems. Because network fragility is an inevitable trade-off of robustness, systems-level understanding is expected to generate therapeutic opportunities to intercept aberrant network activation.
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    Nature Reviews Molecular Cell Biology (2001), 2 (2), 127-137CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)
    A review, with 112 refs. When epidermal growth factor and its relatives bind the ErbB family of receptors, they trigger a rich network of signaling pathways, culminating in responses ranging from cell division to death, motility to adhesion. The network is often dysregulated in cancer and lends credence to the mantra that mol. understanding yields clin. benefit: over 25,000 women with breast cancer have now been treated with Herceptin, a recombinant antibody designed to block the receptor ErbB2. Likewise, small-mol. enzyme inhibitors and monoclonal antibodies to ErbB1 are in advanced phases of clin. testing. What can this pathway teach us about translating basic science into clin. use.
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    Mendelsohn, J.; Baselga, J. Epidermal Growth Factor Receptor Targeting in Cancer. Semin. Oncol. 2006, 33 (4), 369– 385,  DOI: 10.1053/j.seminoncol.2006.04.003
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    Current Opinion in Cell Biology (2007), 19 (2), 124-134CODEN: COCBE3; ISSN:0955-0674. (Elsevier Ltd.)
    A review. The ErbB receptor tyrosine kinases evolved as key regulatory entities enabling the extracellular milieu to communicate with the intracellular machinery to bring forth the appropriate biol. response in an ever-changing environment. Since its discovery, many aspects of the ErbB family have been deciphered, with emphasis on aberration of signaling in human diseases. However, only now, with the availability of the at. coordinates of these receptors, can we construct a comprehensive model of the mechanisms underlying ligand-induced receptor dimerization and subsequent tyrosine kinase activation. Furthermore, the recent introduction of new high-throughput screening methodologies, combined with the materialization of a systems biol. perspective, reveals an overwhelming network complexity, enabling robust signaling and evolvability. This knowledge is likely to impact our view of diseases as system perturbations and resistance to ErbB-targeted therapeutics as manifestations of robustness.
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    Wee, P.; Wang, Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers (Basel). 2017, 9 (5), 52,  DOI: 10.3390/cancers9050052
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    Fuchs, B. C.; Hoshida, Y.; Fujii, T.; Wei, L.; Yamada, S.; Lauwers, G. Y.; Mcginn, C. M.; Deperalta, D. K.; Chen, X.; Kuroda, T.; Lanuti, M.; Schmitt, A. D.; Gupta, S.; Crenshaw, A.; Onofrio, R.; Taylor, B.; Winckler, W.; Bardeesy, N.; Caravan, P.; Golub, T. R.; Tanabe, K. K. Epidermal Growth Factor Receptor Inhibition Attenuates Liver Fibrosis and Development of Hepatocellular Carcinoma. Hepatology 2014, 59 (4), 1577– 1590,  DOI: 10.1002/hep.26898
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    Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma
    Fuchs, Bryan C.; Hoshida, Yujin; Fujii, Tsutomu; Wei, Lan; Yamada, Suguru; Lauwers, Gregory Y.; McGinn, Christopher M.; DePeralta, Danielle K.; Chen, Xintong; Kuroda, Toshihiko; Lanuti, Michael; Schmitt, Anthony D.; Gupta, Supriya; Crenshaw, Andrew; Onofrio, Robert; Taylor, Bradley; Winckler, Wendy; Bardeesy, Nabeel; Caravan, Peter; Golub, Todd R.; Tanabe, Kenneth K.
    Hepatology (Hoboken, NJ, United States) (2014), 59 (4), 1577-1590CODEN: HPTLD9; ISSN:0270-9139. (John Wiley & Sons, Inc.)
    Hepatocellular carcinoma (HCC) is the most rapidly increasing cause of cancer-related mortality in the United States. Because of the lack of viable treatment options for HCC, prevention in high-risk patients has been proposed as an alternative strategy. The main risk factor for HCC is cirrhosis and several lines of evidence implicate epidermal growth factor (EGF) in the progression of cirrhosis and development of HCC. We therefore examd. the effects of the EGF receptor (EGFR) inhibitor erlotinib on liver fibrogenesis and hepatocellular transformation in three different animal models of progressive cirrhosis: a rat model induced by repeated, low-dose injections of diethylnitrosamine (DEN), a mouse model induced by carbon tetrachloride (CCl4), and a rat model induced by bile duct ligation (BDL). Erlotinib reduced EGFR phosphorylation in hepatic stellate cells (HSC) and reduced the total no. of activated HSC. Erlotinib also decreased hepatocyte proliferation and liver injury. Consistent with all these findings, pharmacol. inhibition of EGFR signaling effectively prevented the progression of cirrhosis and regressed fibrosis in some animals. Moreover, by alleviating the underlying liver disease, erlotinib blocked the development of HCC and its therapeutic efficacy could be monitored with a previously reported gene expression signature predictive of HCC risk in human cirrhosis patients. Conclusion: These data suggest that EGFR inhibition using Food and Drug Administration-approved inhibitors provides a promising therapeutic approach for redn. of fibrogenesis and prevention of HCC in high-risk cirrhosis patients who can be identified and monitored by gene expression signatures. (Hepatol. 2014;59:1577-1590).
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    Huang, W. C.; Chan, S. H.; Jang, T. H.; Chang, J. W.; Ko, Y. C.; Yen, T. C.; Chiang, S. L.; Chiang, W. F.; Shieh, T. Y.; Liao, C. T.; Juang, J. L.; Wang, H. C.; Cheng, A. J.; Lu, Y. C.; Wang, L. H. MiRNA-491–5p and GIT1 Serve as Modulators and Biomarkers for Oral Squamous Cell Carcinoma Invasion and Metastasis. Cancer Res. 2014, 74 (3), 751– 764,  DOI: 10.1158/0008-5472.CAN-13-1297
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    miRNA-491-5p and GIT1 Serve as Modulators and Biomarkers for Oral Squamous Cell Carcinoma Invasion and Metastasis
    Huang, Wei-Chieh; Chan, Shih-Hsuan; Jang, Te-Hsuan; Chang, Jer-Wei; Ko, Ying-Chin; Yen, Tzu-Chen; Chiang, Shang-Lun; Chiang, Wei-Fan; Shieh, Tien-Yu; Liao, Chun-Ta; Juang, Jyh-Lyh; Wang, Hsueh-Chun; Cheng, Ann-Joy; Lu, Ya-Ching; Wang, Lu-Hai
    Cancer Research (2014), 74 (3), 751-764CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
    MicroRNAs offer tools to identify and treat invasive cancers. Using highly invasive isogenic oral squamous cell carcinoma (OSCC) cells, established using in vitro and in vivo selection protocols from poorly invasive parental cell populations, we used microarray expression anal. to identify a relative and specific decrease in miR-491-5p in invasive cells. Lower expression of miR-491-5p correlated with poor overall survival of patients with OSCCs. MiR- 491-5p overexpression in invasive OSCC cells suppressed their migratory behavior in vitro and lung metastatic behavior in vivo. We defined the G-proteincoupled receptor kinase-interacting protein I (GITl)as a direct target gene for miR-491-5p control. GITl overexpression was sufficient to rescue miR-491-5p-mediated inhibition of migration/invasion and lung metastasis. Conversely, GITl silencing phenocopied the ability of miR-491-5p to inhibit migration/invasion and metastasis of OSCC cells. Mechanistic investigations indicated that miR-491-5p overexpression or GITl attenuation reduced focal adhesions, with a concurrent decrease in steady-state levels of paxillin, phospho-paxillin, phospho-FAK, EGF/EGFR-mediated extracellular signal-regulated kinase (ERK1/2) activation, and MMP2/9 levels and activities. In clin. specimens of OSCCs, GITl levels were elevated relative to paired normal tissues and were correlated with lymph node metastasis, with expression levels of miR-491-5p and GITI correlated inversely in OSCCs, where they informed tumor grade. Together, our findings identify a functional axis for OSCC invasion that suggests miR-491-5p and GITl as biomarkers for prognosis in this cancer.
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    Zheng, K.; Kitazato, K.; Wang, Y. Viruses Exploit the Function of Epidermal Growth Factor Receptor. Rev. Med. Virol. 2014, 24 (4), 274– 286,  DOI: 10.1002/rmv.1796
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    Viruses exploit the function of epidermal growth factor receptor
    Zheng, Kai; Kitazato, Kaio; Wang, Yifei
    Reviews in Medical Virology (2014), 24 (4), 274-286CODEN: RMVIEW; ISSN:1052-9276. (John Wiley & Sons Ltd.)
    A review. SUMMARY : Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that regulates cellular homeostatic processes. Following ligand binding, EGFR activates different downstream signalling cascades that promote cell survival, proliferation, motility, and angiogenesis and induces F-actin-dependent EGFR endocytosis, which relocalizes the activated receptors for degrdn. or recycling. The responses that are induced by ligand binding to EGFR, including cell signalling activation, protein kinase phosphorylation and cytoskeletal network rearrangement, resemble those induced by virus infection. Increasing evidence demonstrates that many viruses usurp EGFR endocytosis or EGFR-mediated signalling for entry, replication, inflammation, and viral antagonism to the host antiviral system. In addn., viruses have acquired sophisticated mechanisms to regulate EGFR functions by interrupting the EGFR-recycling process and modulating EGFR expression. In this review, we provide an overview of the mechanisms by which viruses alter EGFR signalling in favor of their continued survival.
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  146. 146
    Lupberger, J.; Zeisel, M. B.; Xiao, F.; Thumann, C.; Fofana, I.; Zona, L.; Davis, C.; Mee, C. J.; Turek, M.; Gorke, S.; Royer, C.; Fischer, B.; Zahid, M. N.; Lavillette, D.; Fresquet, J.; Cosset, F. L.; Rothenberg, S. M.; Pietschmann, T.; Patel, A. H.; Pessaux, P.; Dofföl, M.; Raffelsberger, W.; Poch, O.; McKeating, J. A.; Brino, L.; Baumert, T. F. EGFR and EphA2 Are Host Factors for Hepatitis C Virus Entry and Possible Targets for Antiviral Therapy. Nat. Med. 2011, 17 (5), 589– 595,  DOI: 10.1038/nm.2341
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    EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy
    Lupberger, Joachim; Zeisel, Mirjam B.; Xiao, Fei; Thumann, Christine; Fofana, Isabel; Zona, Laetitia; Davis, Christopher; Mee, Christopher J.; Turek, Marine; Gorke, Sebastian; Royer, Cathy; Fischer, Benoit; Zahid, Muhammad N.; Lavillette, Dimitri; Fresquet, Judith; Cosset, Francois-Loic; Rothenberg, S. Michael; Pietschmann, Thomas; Patel, Arvind H.; Pessaux, Patrick; Doffoel, Michel; Raffelsberger, Wolfgang; Poch, Olivier; McKeating, Jane A.; Brino, Laurent; Baumert, Thomas F.
    Nature Medicine (New York, NY, United States) (2011), 17 (5), 589-595CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
    Hepatitis C virus (HCV) is a major cause of liver disease, but therapeutic options are limited and there are no prevention strategies. Viral entry is the first step of infection and requires the cooperative interaction of several host cell factors. Using a functional RNAi kinase screen, we identified epidermal growth factor receptor and ephrin receptor A2 as host cofactors for HCV entry. Blocking receptor kinase activity by approved inhibitors broadly impaired infection by all major HCV genotypes and viral escape variants in cell culture and in a human liver chimeric mouse model in vivo. The identified receptor tyrosine kinases (RTKs) mediate HCV entry by regulating CD81-claudin-1 co-receptor assocns. and viral glycoprotein-dependent membrane fusion. These results identify RTKs as previously unknown HCV entry cofactors and show that tyrosine kinase inhibitors have substantial antiviral activity. Inhibition of RTK function may constitute a new approach for prevention and treatment of HCV infection.
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    Zona, L.; Lupberger, J.; Sidahmed-Adrar, N.; Thumann, C.; Harris, H. J.; Barnes, A.; Florentin, J.; Tawar, R. G.; Xiao, F.; Turek, M.; Durand, S. C.; Duong, F. H. T.; Heim, M. H.; Cosset, F. L.; Hirsch, I.; Samuel, D.; Brino, L.; Zeisel, M. B.; Le Naour, F.; McKeating, J. A.; Baumert, T. F. HRas Signal Transduction Promotes Hepatitis C Virus Cell Entry by Triggering Assembly of the Host Tetraspanin Receptor Complex. Cell Host Microbe 2013, 13 (3), 302– 313,  DOI: 10.1016/j.chom.2013.02.006
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    HRas Signal Transduction Promotes Hepatitis C Virus Cell Entry by Triggering Assembly of the Host Tetraspanin Receptor Complex
    Zona, Laetitia; Lupberger, Joachim; Sidahmed-Adrar, Nazha; Thumann, Christine; Harris, Helen J.; Barnes, Amy; Florentin, Jonathan; Tawar, Rajiv G.; Xiao, Fei; Turek, Marine; Durand, Sarah C.; Duong, Francois H. T.; Heim, Markus H.; Cosset, Francois-Loic; Hirsch, Ivan; Samuel, Didier; Brino, Laurent; Zeisel, Mirjam B.; Le Naour, Francois; McKeating, Jane A.; Baumert, Thomas F.
    Cell Host & Microbe (2013), 13 (3), 302-313CODEN: CHMECB; ISSN:1931-3128. (Elsevier Inc.)
    Hepatitis C virus (HCV) entry is dependent on coreceptor complex formation between the tetraspanin superfamily member CD81 and the tight junction protein claudin-1 (CLDN1) on the host cell membrane. The receptor tyrosine kinase EGFR acts as a cofactor for HCV entry by promoting CD81-CLDN1 complex formation via unknown mechanisms. We identify the GTPase HRas, activated downstream of EGFR signaling, as a key host signal transducer for EGFR-mediated HCV entry. Proteomic anal. revealed that HRas assocs. with tetraspanin CD81, CLDN1, and the previously unrecognized HCV entry cofactors integrin β1 and Ras-related protein Rap2B in hepatocyte membranes. HRas signaling is required for lateral membrane diffusion of CD81, which enables tetraspanin receptor complex assembly. HRas was also found to be relevant for entry of other viruses, including influenza. Our data demonstrate that viruses exploit HRas signaling for cellular entry by compartmentalization of entry factors and receptor trafficking.
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    Baktash, Y.; Madhav, A.; Coller, K. E.; Randall, G. Single Particle Imaging of Polarized Hepatoma Organoids upon Hepatitis C Virus Infection Reveals an Ordered and Sequential Entry Process. Cell Host Microbe 2018, 23 (3), 382– 394, e5  DOI: 10.1016/j.chom.2018.02.005
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    Single Particle Imaging of Polarized Hepatoma Organoids upon Hepatitis C Virus Infection Reveals an Ordered and Sequential Entry Process
    Baktash, Yasmine; Madhav, Anisha; Coller, Kelly E.; Randall, Glenn
    Cell Host & Microbe (2018), 23 (3), 382-394.e5CODEN: CHMECB; ISSN:1931-3128. (Elsevier Inc.)
    Hepatitis C virus (HCV) enters hepatocytes via various entry factors, including scavenger receptor BI (SR-B1), cluster of differentiation 81 (CD81), epidermal growth factor receptor (EGFR), claudin-1 (CLDN1), and occludin (OCLN). As CLDN1 and OCLN are not readily accessible due to their tight junctional localization, HCV likely accesses them by either disrupting cellular polarity or migrating to the tight junction. In this study, we image HCV entry into a three-dimensional polarized hepatoma system and reveal that the virus sequentially engages these entry factors through actin-dependent mechanisms. HCV initially localizes with the early entry factors SR-B1, CD81, and EGFR at the basolateral membrane and then accumulates at the tight junction in an actin-dependent manner. HCV assocs. with CLDN1 and then OCLN at the tight junction and is internalized via clathrin-mediated endocytosis by an active process requiring EGFR. Thus, HCV uses a dynamic and multi-step process to engage and enter host cells.
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    Diao, J.; Pantua, H.; Ngu, H.; Komuves, L.; Diehl, L.; Schaefer, G.; Kapadia, S. B. Hepatitis C Virus Induces Epidermal Growth Factor Receptor Activation via CD81 Binding for Viral Internalization and Entry. J. Virol. 2012, 86 (20), 10935,  DOI: 10.1128/JVI.00750-12
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    Hepatitis C virus induces epidermal growth factor receptor activation via CD81 binding for viral internalization and entry
    Diao, Jingyu; Pantua, Homer; Ngu, Hai; Komuves, Laszlo; Diehl, Lauri; Schaefer, Gabriele; Kapadia, Sharookh B.
    Journal of Virology (2012), 86 (20), 10935-10949CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
    While epidermal growth factor receptor (EGFR) has been shown to be important in the entry process for multiple viruses, including hepatitis C virus (HCV), the mol. mechanisms by which EGFR facilitates HCV entry are not well understood. Using the infectious cell culture HCV model (HCVcc), we demonstrate that the binding of HCVcc particles to human hepatocyte cells induces EGFR activation that is dependent on interactions between HCV and CD81 but not claudin 1. EGFR activation can also be induced by antibody mediated crosslinking of CD81. In addn., EGFR ligands that enhance the kinetics of HCV entry induce EGFR internalization and colocalization with CD81. While EGFR kinase inhibitors inhibit HCV infection primarily by preventing EGFR endocytosis, antibodies that block EGFR ligand binding or inhibitors of EGFR downstream signaling have no effect on HCV entry. These data demonstrate that EGFR internalization is crit. for HCV entry and identify a hitherto-unknown assocn. between CD81 and EGFR.
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    Mailly, L.; Xiao, F.; Lupberger, J.; Wilson, G. K.; Aubert, P.; Duong, F. H. T.; Calabrese, D.; Leboeuf, C.; Fofana, I.; Thumann, C.; Bandiera, S.; Lütgehetmann, M.; Volz, T.; Davis, C.; Harris, H. J.; Mee, C. J.; Girardi, E.; Chane-Woon-Ming, B.; Ericsson, M.; Fletcher, N.; Bartenschlager, R.; Pessaux, P.; Vercauteren, K.; Meuleman, P.; Villa, P.; Kaderali, L.; Pfeffer, S.; Heim, M. H.; Neunlist, M.; Zeisel, M. B.; Dandri, M.; McKeating, J. A.; Robinet, E.; Baumert, T. F. Clearance of Persistent Hepatitis C Virus Infection in Humanized Mice Using a Claudin-1-Targeting Monoclonal Antibody. Nat. Biotechnol. 2015, 33 (5), 549– 554,  DOI: 10.1038/nbt.3179
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    Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody
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    Nature Biotechnology (2015), 33 (5), 549-554CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
    Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and cancer. Cell entry of HCV and other pathogens is mediated by tight junction (TJ) proteins, but successful therapeutic targeting of TJ proteins has not been reported yet. Using a human liver-chimeric mouse model, we show that a monoclonal antibody specific for the TJ protein claudin-1 (ref. 7) eliminates chronic HCV infection without detectable toxicity. This antibody inhibits HCV entry, cell-cell transmission and virus-induced signaling events. Antibody treatment reduces the no. of HCV-infected hepatocytes in vivo, highlighting the need for de novo infection by means of host entry factors to maintain chronic infection. In summary, we demonstrate that an antibody targeting a virus receptor can cure chronic viral infection and uncover TJ proteins as targets for antiviral therapy.
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    Igloi, Z.; Kazlauskas, A.; Saksela, K.; MacDonald, A.; Mankouri, J.; Harris, M. Hepatitis C Virus NS5A Protein Blocks Epidermal Growth Factor Receptor Degradation via a Proline Motif- Dependent Interaction. J. Gen. Virol. 2015, 96 (8), 2133– 2144,  DOI: 10.1099/vir.0.000145
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    Hepatitis C virus NS5A protein blocks epidermal growth factor receptor degradation via a proline motif- dependent interaction
    Igloi, Zsofia; Kazlauskas, Arunas; Saksela, Kalle; MacDonald, Andrew; Mankouri, Jamel; Harris, Mark
    Journal of General Virology (2015), 96 (8), 2133-2144CODEN: JGVIAY; ISSN:0022-1317. (Society for General Microbiology)
    Hepatitis C virus (HCV) establishes a persistent infection that in many cases leads to cirrhosis and hepatocellular carcinoma. The non-structural 5A protein (NS5A) has been implicated in this process as it contains a C-terminal polyproline motif (termed P2) that binds to Src homol. 3 (SH3) domains to regulate cellular signalling and trafficking pathways. We have shown previously that NS5A impaired epidermal growth factor (EGF) receptor (EGFR) endocytosis, thereby inhibiting EGF-stimulated EGFR degrdn. by a mechanism that remained unclear. As EGFR has been implicated in HCV cell entry and trafficking of the receptor involves several SH3-domain contg. proteins, we investigated in more detail the mechanisms by which NS5A perturbs EGFR trafficking. We demonstrated that the P2 motif was required for the NS5A-mediated disruption to EGFR trafficking. We further demonstrated that the P2 motif was required for an interaction between NS5A and CMS, a homolog of CIN85 that has previously been implicated in EGFR endocytosis. We provided evidence that CMS was involved in the NS5A-mediated perturbation of EGFR trafficking. We also showed that NS5A effected a loss of EGFR ubiquitination in a P2-motif-dependent fashion. These data provide clues to the mechanism by which NS5A regulates the trafficking of a key cellular receptor and demonstrate for the first time the ability of NS5A to regulate host cell ubiquitination pathways.
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    Xu, X.; Zheng, L.; Yuan, Q.; Zhen, G.; Crane, J. L.; Zhou, X.; Cao, X. Transforming Growth Factor-β in Stem Cells and Tissue Homeostasis. Bone Res. 2018, 6 (1), 2,  DOI: 10.1038/s41413-017-0005-4
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    Transforming growth factor-β in stem cells and tissue homeostasis
    Xu Xin; Zhou Xuedong; Zheng Liwei; Yuan Quan; Zhen Gehua; Crane Janet L; Cao Xu; Crane Janet L
    Bone research (2018), 6 (), 2 ISSN:2095-4700.
    TGF-β 1-3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix (ECM). The biological functions of TGF-β in adults can only be delivered after ligand activation, mostly in response to environmental perturbations. Although involved in multiple biological and pathological processes of the human body, the exact roles of TGF-β in maintaining stem cells and tissue homeostasis have not been well-documented until recent advances, which delineate their functions in a given context. Our recent findings, along with data reported by others, have clearly shown that temporal and spatial activation of TGF-β is involved in the recruitment of stem/progenitor cell participation in tissue regeneration/remodeling process, whereas sustained abnormalities in TGF-β ligand activation, regardless of genetic or environmental origin, will inevitably disrupt the normal physiology and lead to pathobiology of major diseases. Modulation of TGF-β signaling with different approaches has proven effective pre-clinically in the treatment of multiple pathologies such as sclerosis/fibrosis, tumor metastasis, osteoarthritis, and immune disorders. Thus, further elucidation of the mechanisms by which TGF-β is activated in different tissues/organs and how targeted cells respond in a context-dependent way can likely be translated with clinical benefits in the management of a broad range of diseases with the involvement of TGF-β.
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    Chaudhury, A.; Howe, P. H. The Tale of Transforming Growth Factor-β (TGFβ) Signaling: A Soigné Enigma. IUBMB Life 2009, 61 (10), 929,  DOI: 10.1002/iub.239
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    The tale of transforming growth factor-beta (TGFβ) signaling: A soigne enigma
    Chaudhury, Arindam; Howe, Philip H.
    IUBMB Life (2009), 61 (10), 929-939CODEN: IULIF8; ISSN:1521-6543. (John Wiley & Sons Inc.)
    A review. Transforming growth factor-beta (TGFβ) is a secreted cytokine, which intricately controls a plethora of physiol. and pathol. processes during development and carcinogenesis. TGFβ exerts antiproliferative effects and functions as a tumor suppressor during early stages of tumorigenesis, whereas at later stages it functions as a tumor promoter aiding in metastatic progression through an autocrine TGFβ loop. Intricate knowledge of TGFβ signaling and its regulation are still evolving. In this review, we make an attempt to showcase the assocd. enigma of TGFβ signaling in its dual functional role as tumor suppressor and metastatic promoter during early and late stages of carcinogenesis, resp. © 2009 IUBMB IUBMB Life, 61(10): 929-939, 2009.
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    Miyazawa, K.; Shinozaki, M.; Hara, T.; Furuya, T.; Miyazono, K. Two Major Smad Pathways in TGF-Beta Superfamily Signalling. Genes Cells 2002, 7 (12), 1191– 1204,  DOI: 10.1046/j.1365-2443.2002.00599.x
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    Two major Smad pathways in TGF-β superfamily signalling
    Miyazawa, Keiji; Shinozaki, Masahiko; Hara, Takane; Furuya, Toshio; Miyazono, Kohei
    Genes to Cells (2002), 7 (12), 1191-1204CODEN: GECEFL; ISSN:1356-9597. (Blackwell Science Ltd.)
    A review. Members of the transforming growth factor-β (TGF-β) superfamily bind to two different serine/threonine kinase receptors, i.e., type I and type II receptors. Upon ligand binding, type I receptors specifically activate intracellular Smad proteins. R-Smads are direct substrates of type I receptors; Smads 2 and 3 are specifically activated by activin/nodal and TGF-β type I receptors, whereas Smads 1, 5 and 8 are activated by BMP type I receptors. Nearly 30 proteins have been identified as members of the TGF-β superfamily in mammals, and can be classified based on whether they activate activin/TGF-β-specific R-Smads (AR-Smads) or BMP-specific R-Smads (BR-Smads). R-Smads form complexes with Co-Smads and translocate into the nucleus, where they regulate the transcription of target genes. AR-Smads bind to various proteins, including transcription factors and transcriptional co-activators or co-repressors, whereas BR-Smads interact with other proteins less efficiently than AR-Smads. Id proteins are induced by BR-Smads, and play important roles in exhibiting some biol. effects of BMPs. Understanding the mechanisms of TGF-β superfamily signaling is thus important for the devel