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ELIZABETH WILSON

An AIDS research group reports that it has identified an elusive antiviral factor secreted by immune cells of HIV-resistant people—a discovery that, if true, could be revolutionary in its implications for treatment of the disease.

However, other AIDS researchers say the jury is still out and that more research needs to be done before that claim can be made definitively.

Virologist and Rockefeller University assistant professor Linqi Zhang and famed AIDS researcher David D. Ho at the Aaron Diamond AIDS Research Center in New York City and their colleagues have isolated a cluster of small proteins known as human -defensins from CD8 immune system cells of HIV-resistant people [Science, published online Sept. 26, http://www.sciencemag.org/cgi/content/abstract/1076185].

ELUSIVE Ho and coworkers may have discovered what prevents some infected people from getting AIDS.
ROCKEFELLER UNIVERSITY PHOTO

The team says the defensins are the “CD8 antiviral factor” (CAF), first postulated in 1986 by University of California, San Francisco, AIDS researcher Jay A. Levy. While studying people who remained infected with HIV for years without developing AIDS, Levy found that their CD8 T cells—a type of white blood cell that kills virus-infected cells—appeared to secrete an antiviral substance.

Researchers hoped that CAF, if it could be identified and isolated, could be used to help inhibit HIV replication, and perhaps even eradicate the virus. Numerous labs, therefore, have attempted to characterize CAF, but without success.

Human a-defensins-1, -2, and -3 have now been identified with a protein chip and mass spectrometry analysis system from Fremont, Calif.-based Ciphergen Biosystems. Ciphergen scientists are coauthors on the Science paper. It was already known that defensins are produced by other immune cells and have a modest anti-HIV effect in some cases. But the discovery that CD8 cells could also produce defensins was a surprise.

“It’s a very nicely done piece of research,” says Susan Plaeger, chief of pathogenesis and basic research in the Division of AIDS at NIH’s National Institute of Allergies & Infectious Diseases. “The use of chip technology and mass spectrometry is very exciting—it opens the door for people to use this type of technology to keep looking at cells to see what factors they’re making.”

However, Plaeger says she does not think defensins are the only component of CAF. “I think a lot of the controversy is in the use of different cell systems, and the way [researchers] set up cell cultures,” she says. “In a somewhat different system, maybe other molecules will be discovered.”

Levy is more skeptical: He notes that the process of stimulating the CD8 cells—coaxing them into an active, immune-substance-producing state—involves immersing them in a culture that contains other defensin-producing cells. Thus, the defensins that appear to come from the CD8 cells could merely be contamination, he says.

But Zhang says he and his colleagues have performed additional experiments, not reported in the paper, in which they stimulated CD8 cells in a culture without any defensin-producing cells. “So the defensins could not have come from any other source except CD8,” he says.

The researchers are now working to elucidate the antiviral mechanism of defensins and to augment the potency of their anti-HIV effect. “We are obviously interested to see if this discovery could be transformed into therapeutics,” Ho says.

STIMULATED CD8 immune cells (nuclei in blue, proteins in red) produce -defensins (green)— possible anti-HIV factors.
© Science 2002