An hour-long telephone call-in press briefing Thursday drew 21 science journalists from the national and international media. It included major television channels, wire services, news magazines and newspapers.

The callers were drawn by an advance online paper in Sciencexpress dated Sept. 26, 2002. Its title: "Contribution of human a-defensin-1, -2 and -3 to the anti-HIV-1 activity of CD8 antiviral factor." The article's lead author is Linqi Zhang at the Rockefeller University-affiliated Aaron Diamond AIDS Research Center in New York. David Ho, ADARC's director, is senior author of the journal article. He and Zhang officiated at the briefing.

The technical paper revealed a highly compelling mystery, solved by the article: How is it that a small fraction of people infected with the AIDS virus can shrug off its symptoms and dire outcome?

"In 1995 there was a very exciting development," Ho said, "when it was reported that beta-chemokines released from CD8 T cells were capable of suppressing HIV. At first, it seemed that the mystery was solved. However, it was later shown that beta-chemokines only blocked the replication of certain HIV-1s, but not other HIV-1s. And other groups went on to show that one could in fact eliminate beta-chemokines from the CD8 T-cell supernatant, but there's still anti-HIV activity remaining.

"In essence," Ho summed up, "the mystery continued."

From Australia, A Lengthy Case In Point

On this score, an Australian homosexual man made HIV history a decade or more ago. Sexually active, he ignored safe sex with multiple female and male partners, indulged in anal intercourse and shared narcotic needles. Although carrying the viral infection in his blood, this individual, now in his middle years, has remained free of AIDS symptoms for years.

His prolonged defiance of a high-risk gay lifestyle marks this maverick survivor as a long-term non-progressor (LTNP), meaning he has not progressed from HIV to AIDS. LTNPs number 1 percent to 2 percent of HIV-infected patients living with AIDS in the U.S. How do they achieve this seemingly HIV-proof immunity? In fact, the Australian poster boy is not entirely home free. In 1992, he experienced transient symptoms of infection. At that time, his CD4 T lymphocyte count was only 960 (41 percent of normal). By late 1996, it had dropped by half - to 460.

CD4-positive T cells in the body's immune system are notorious as the bull's-eye target of HIV attack, which destroys antiviral immune defenses. One favored clue to the secret of how non-progressors flout HIV and go on living pits CD4⁺ T cells against their counterpart CD8⁺ T lymphocytes. CD4 receptors perch on the surfaces of immune-defense white blood cells, notably neutrophils - one of those white blood cells that kill invading pathogens. CD8 receptors secrete one or more factors that inhibit the immune system's defense mechanisms against HIV. This may explain why some HIV-positive patients progress more than others to full-blown AIDS.

Now a new player, aptly named defensin, takes a hand in the non-progressor game, with the aim of preventing HIV from replicating in the body. Defensins are antibiotic polypeptides found in neutrophils. "This discovery is a major step forward in our understanding of how the body fights HIV," Zhang told the press briefing. "By understanding how some people's immune systems are able to control HIV infection, we may be able to develop new treatments that take advantage of this phenomenon. Despite extensive research efforts," he added, "the identity of the HIV-fighting factors remained elusive until today's announcement in Sciencexpress.

"Scientists have known since 1986," Zhang recounted, "that the human body's CD8 T cells can produce unidentified factors capable of inhibiting HIV replication. In particular, the CD8 T cells of the small percentage of long-term non-progressors can produce high concentrations of these CD8 antiviral factors, which we call CAF,' a soluble factor secreted by CD8⁺ cytotoxic T lymphocytes. CAF may help their bodies keep HIV under control despite prolonged infection. In spite of extensive research over the years," he pointed out, "CAF's identity has been a mystery until today.

"The anti-HIV alpha-defensin proteins identified in the Sciencexpress study," Zhang pointed out, "proved active against all strains of the virus. So our findings suggest that those defensins may have therapeutic applications for people living with AIDS."

Genomics, Proteomics Come To Fore

To this perspective, commented Ho, "Alpha-defensins are promising as a future addition to the HIV treatment arsenal. Our researchers are already pursuing new therapeutic approaches based on the data published today. They evaluated the anti-HIV potency of the defensins by testing synthetic versions of the proteins, as well as purified defensins derived from human immune lymphocytes. They are currently working to improve the potency of the proteins by genomic and proteomic techniques."

As the paper reported, the co-authors are using a novel, chip-based protein analysis system called ProteinChip to compare CD8 T cells from long-term non-progressors with cells from HIV patients whose immune systems had begun to fail. ProteinChip, developed by Ciphergen Biosystems Inc., of Fremont, Calif., allowed them to identify and characterize the defensins much faster and with greater sensitivity than traditional methods allow. Alpha-defensin-1, -2 and -3 were found in all of the patients who remained healthy, but in none whose infections had progressed.

Of the paper's 13 co-authors, five were scientists and technicians on the staff of Ciphergen. That company and ADARC signed a research and licensing agreement in February to pursue projects related to discoveries and samples provided by Aaron Diamond. As part of this pact, Ciphergen retains therapeutic and diagnostic rights to discoveries made under the collaboration, with royalties paid back to ADARC.

"To confirm that these three proteins were responsible for controlling the virus," Zhang went on, "we artificially stripped the alpha-defensins from proteins made by CD8 T cells taken from long-term non-progressors, and found that their anti-HIV activity was virtually eliminated.

"In conclusion," Ho told the briefing session, "I think we are most gratified that this work has helped to solve a big part of the mystery surrounding CAF that's been around for so long. But we wish to be somewhat cautious about the translation of the discovery. It is not entirely clear whether we could turn it into a useful therapeutic."