San Francisco Chronicle - Friday, September 27, 2002
Sabin Russell, Chronicle Medical Writer

But Dr. Jay A. Levy, the UCSF virologist who started the quest for the mysterious antiviral molecule in 1986, believes that Ho is simply mistaken and that his finding is the result of laboratory error.

Regardless, the report released Thursday in the online issue of the journal Science is certain to focus additional research on the factor, which is believed to have kept a rare group of HIV-infected people perfectly healthy for as long as a quarter-century.

Finding how to duplicate the apparent natural immunity of these lucky few is a crucial goal of AIDS research. It may hold the key to a vaccine or drug therapy that could give all AIDS patients hopes for normal life spans.

"Many labs around the country are retooling, as we speak, to jump into this field," said Carl Dieffenbach, an AIDS research specialist at the National Institute of Allergy and Infectious Diseases.

In a telephone briefing with reporters, Ho stressed that it would still take years of research to convert his findings into useful therapies. He cautioned that the factor he found has chemical traits that would make it difficult to manufacture, make into a vaccine, or use for gene therapy.

"This is not going to be the ultimate solution, but it is another weapon we can use in our arsenal against HIV," said Ho, who was named Time magazine's Man of the Year in 1996 for his work developing drug combinations that dramatically reduced AIDS deaths.

FREMONT FIRM COULD BENEFIT

If the findings are confirmed by other researchers, Ho's paper also will represent a major coup for Ciphergen Biosystems Inc., a Fremont company that made the sophisticated laboratory tools used to solve the problem. Ciphergen scientists co-wrote the paper with Ho and his colleagues at the Aaron Diamond AIDS Research Center in New York.

Ho's team believes that the long-sought factor is, in fact, a trio of tiny proteins called "defensins." The big surprise to biologists is that defensins are relatively well-known and relatively common.

Discovered in 1984, they are chemical weapons used by a class of white blood cells that kill and eat bacteria. Their activity against viruses was thought to be limited.

Linqui Zhang, a Rockefeller University professor and scientist in Ho's lab, thought up the idea of using Ciphergen's new technology to find the elusive antiviral factor. The machine can detect distinct chemical signatures for each protein component in a sample of cells. Zhang decided to analyze CD-8 cells, specialized white blood cells that Levy had shown in 1986 produced the mysterious protective factor, which he called CAF.

Zhang compared blood cells from subjects who were infected with HIV but were otherwise healthy with those of other HIV patients who had developed AIDS.

The machine detected a small but distinct difference in the blood cells that came from members of the healthy group, who are called "long-term non- progressors" because their infection does not develop into AIDS.

When members of Ho's group analyzed that signature -- three small spikes on a graph -- they realized it was identical to the signature produced by three different defensins. Using multiple tests, they confirmed that defensins were indeed the protein that was detected in the healthy subjects' blood.

"We completed the circle," Ho said. ". . . The most gratifying thing is solving a big part of this mystery. I don't think we want to claim we solved everything."

PURITY OF CELLS DISPUTED

But UCSF's Levy, an acclaimed virologist who was one of the first to isolate the AIDS virus, said he thinks Ho has made a fundamental blunder.

Levy discovered in 1986 that long-term non-progressors were protected from HIV by a class of white blood cells called CD-8s. He coined the term CAF, or "CD-8 Antiviral Factor," for the unknown chemical produced by CD-8s that was fending off the virus.

Ho's experiment, he said, has certainly pinpointed defensins. But Levy said he believes those proteins may have come from different blood cells used in the preparation of the experiment -- in short, laboratory contamination.

"If this is CD-8 antiviral factor, we need to know it is made by CD-8 cells, " Levy said. It could have come from other white blood cells that make lots of defensins and are used in the lab to help grow CD-8s.

UC Irvine pathologist Dr. Michael Selsted, an expert in defensins, shares similar concerns. Proving that the defensins came from CD-8s, he said, "is a simple, one-afternoon experiment," and he is puzzled that such sophisticated researchers didn't include it in their paper.

But according to Zhang, the issue of contamination was addressed in a subsequent experiment. Although the results of that experiment are unpublished, Zhang said they confirmed that CD-8 cells were producing defensins.

Other scientists are taking a wait-and-see attitude: "David (Ho) did all the right experiments. Whether or not this turns out to be the exact thing Jay (Levy) is looking for will come out in the wash," Dieffenbach said.

E-mail Sabin Russell at srussell@sfchronicle.com.

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