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Probing the Molecular Mechanisms of AZT Drug Resistance Mediated by HIV-1 Reverse Transcriptase Using a Transient Kinetic Analysis

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    Probing the Molecular Mechanisms of AZT Drug Resistance Mediated by HIV-1 Reverse Transcriptase Using a Transient Kinetic Analysis†
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    Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, Georgia 30602-2352, and Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine/Veterans Affairs Medical Center, Decatur, Georgia 30033
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    Biochemistry

    Cite this: Biochemistry 2003, 42, 29, 8831–8841
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    https://doi.org/10.1021/bi034435l
    Published July 4, 2003
    Copyright © 2003 American Chemical Society
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    Abstract

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    Several hypotheses have been proposed to explain the development of resistance to the anti-HIV drug AZT. Clinical findings show that AZT resistance mutations in HIV-1 reverse transcriptase (RT) not only reduce susceptibility to thymidine analogues but may also confer multi-dideoxynucleoside resistance. In this report, we describe transient kinetic studies establishing the biochemical effects of AZT resistance mutations in HIV-1 RT on the incorporation and removal of natural and unnatural deoxynucleotides. While the physiological role remains to be elucidated, the largest biochemical difference between wild-type and AZT resistant HIV-1 RT manifested itself during ATP-mediated deoxynucleotide removal. Enhanced removal resulted from an increase in the maximum rate of chain terminator excision, suggesting that mutated residues play a role in the optimal alignment of substrates for ATP-mediated removal. The efficiency of pyrophosphorolysis was not increased by the presence of AZT resistance mutations. However, a 2-fold decrease in the extent of inhibition caused by the next correct nucleotide during pyrophosphorolytic cleavage of a D4TMP chain-terminated primer may illustrate how this mutant can utilize pyrophosphate to enhance resistance. The inability of RT to catalyze removal of a chain terminator from an RNA−RNA primer−template may show how slight changes in selectivity against AZTMP incorporation during the initiation of DNA synthesis can contribute to high-level resistance. Taken together, these results suggest that multiple modes of resistance may be conferred by these mutations. Structure−activity studies of chain terminator removal suggest that analogues that form tight interactions with residues in the RT active site may be more prone to resistance mechanisms mediated by removal.

    Copyright © 2003 American Chemical Society

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    †

     Work supported by NIH Grants GM49551 (K.S.A.), R37AI-41980 (R.F.S.), AI 25899 (C.K.C.), and RO1AI-32351 (R.F.S. and C.K.C.), the Department of Veteran Affairs (R.F.S.), NRSA 5 T32 GM07223 from the National Institute of General Medical Sciences (A.S.R.), and ACS Postdoctoral Fellowship PF-4478 (J.A.V.).

    ‡

     Yale University School of Medicine.

    §

     Current address:  Department of Biochemistry, Tulane University Health Sciences Center, 1430 Tulane Ave. SL-43, New Orleans, LA 70112.

    ‖

     The University of Georgia.

    ⊥

     Emory University School of Medicine/Veterans Affairs Medical Center.

    *

     To whom correspondence should be addressed. E-mail:  [email protected]. Phone:  (203) 785-4526. Fax:  (203) 785-7670.

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    Biochemistry

    Cite this: Biochemistry 2003, 42, 29, 8831–8841
    Click to copy citationCitation copied!
    https://doi.org/10.1021/bi034435l
    Published July 4, 2003
    Copyright © 2003 American Chemical Society
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