Wall Street Journal - September 27, 2002
Marilyn Chase Staff Reporter of The Wall Street Journal

Discovering how 1% or 2% of infected people keep the powerful virus at bay has inspired a race by some of the biggest names in AIDS research. Now, in a finding that could open up new fields of inquiry into fighting HIV, a team of scientists claims to have found the answer.

The scientists say they have discovered that three proteins -- alpha-defensins 1, 2 and 3 -- have an anti-HIV role. The proteins are secreted by two types of white blood cells in the immune system, known as CD8 T-cells and neutrophils, the scientists say. And it is these proteins, they say, that play a primary role in suppressing AIDS in the HIV survivors, who are technically called "long-term nonprogressors," and who have shown no sign of suppressed immunity after as many as 20 years of infection.

The discovery, described in the current issue of the journal Science, was made by a team led by David Ho and Linqi Zhang of the Aaron Diamond AIDS Research Center, a nonprofit AIDS research corporation in New York. The team also included scientists working at Rockefeller University in New York, and at Ciphergen Biosystems Inc. of Fremont, Calif. Dr. Ho, scientific director and chief executive of the Diamond center, is already a celebrity AIDS scientist, having landed on the cover of Time magazine in 1996 after his studies in virology helped to pave the way for the current generation of drug-cocktail therapy.

But the scientists caution that it could be many years, if ever, before the discovery described in Science leads to new treatments. And as is usual in the world of AIDS research, word of the finding immediately generated skepticism and debate among competing scientists, who question whether the key to the patients' resistance to AIDS has really been discovered.

"This is not it. I'll be frank," says Jay A. Levy, professor of medicine and director of the Laboratory for Tumor and AIDS Virus Research at the University of California at San Francisco. In 1986, Dr. Levy reported the phenomenon of long-term nonprogressors, and in 1990 he described the cause as a factor secreted by CD8 cells. But the identity of that factor remains elusive, he says.

Many natural substances with antiviral actions have come and gone as candidates for the CD8 factor. "I wish we had the answer," Dr. Levy says. "We know it's secreted by CD8 cells, and we know it blocks transcription of the virus -- that is, it blocks the virus after it enters the cell, so that it can't make its RNA, its genomic material."

Dr. Levy says his skepticism was intensified by questions about the potency of the defensins' antiviral effect, and doubts about whether their source was truly CD8 cells. The defensins cited by Drs. Ho and Zhang came not just from CD8 cells but also from other white blood cells called neutrophils, leading Dr. Levy to say, "I'm afraid they've got contamination here."

Cautious but confident, Dr. Ho nonetheless maintains that his defensins exert 90% of the antiviral effect that keeps long-term nonprogressors alive despite an onslaught by a type of HIV known as X4 virus. "We would simply let other investigators in the field read our paper and make their own decisions," he says. "We don't say this accounts for all of [the antiviral effects reported by Dr. Levy]. But it is a principal contributor."

Another prominent AIDS researcher, HIV co-discoverer Robert Gallo, previously found substances called chemo-kines that exert antiviral effects against a subgroup of HIV called R5 viruses. Earlier this year, Dr. Gallo asserted that he had found three HIV inhibitors, possibly explaining the mystery of long-term nonprogressors, but his findings haven't been published yet. Dr. Gallo couldn't be reached to comment.

Alpha-defensins may be candidates for drug development, Dr. Ho says, adding, "This is a major direction of research for the future. We'd like to see whether there's clinical activity."

But he adds that his group has yet to determine the defensins' mechanism of action, and to find ways to boost their strength -- two of the many hurdles that must be cleared before the defensins can become clinically useful. The proteins, which are also found in healthy, uninfected people, may have a role in fighting off the infection in the first place, says a spokesman for the researchers, adding that they are uncomfortable speculating about how the proteins might work.

Drs. Ho and Zhang say that it will be technically difficult to manufacture defensins because the proteins are formed by long chains of 29 or 30 amino acids that are intricately folded into patterns whose shape helps determine their antiviral action in the body. "It would be wrong to say we now have a new therapeutic," Dr. Ho acknowledges. "It's going to take at least a few years to see if this has utility."

Write to Marilyn Chase at marilyn.chase@wsj.com
020927
WJ020908

Copyright © 2002 - The Wall Street Journal. Reproduction of this article (other than one copy for personal reference) must be cleared through the WSJ Permissions Desk.

Always watch for outdated information. This article first appeared in 2002. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 2002. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .