San Francisco Chronicle - Tuesday, January 5, 1999
Carl T. Hall, Chronicle Science Writer

That runs counter to the widely held view among AIDS scientists that HIV strikes mainly by killing T cells, the body's front-line defenders, as fast as the immune system can produce them.

The controversial new findings include the first direct measurements showing how the human immune system becomes locked in a lethal battle with the AIDS virus.

The results challenge a core tenet in the scientific dogma of AIDS, a view that has dominated the field ever since a landmark 1995 study co-authored by famed New York AIDS expert David Ho.

The Ho group's research pictured the AIDS virus as a virulent attacker that destroys immune cells by the millions, which spurs a flood of new cells --which also become infected and die.

In the end, according to this view, the immune system collapses from exhaustion. That leaves the infected victims vulnerable to all the deadly opportunistic diseases that mark the AIDS syndrome.

The new study, published yesterday in the journal Nature Medicine, suggests a fundamentally different process at work. The study appears along with two separate reports on promising but very early-stage experimental approaches to treating the disease.

Taken together, the studies foretell a new generation of immune- system targeted AIDS therapies, experts said. Given the the growing problem of drug-resistant strains of HIV, they note, such new weapons in the AIDS battle are vitally important.

"We definitely need new approaches," said Dr. Warner Greene, director of the Gladstone Institute of Virology and Immunology at the University of California at San Francisco.

Researchers affiliated with the Gladstone Institute and the University of California at Berkeley suggest that the previous theory, with its presumed flurry of T-cell output, was an illusion of faulty assumptions and poor measurement techniques.

The Bay Area scientists used a newly developed molecular tag to track the ebb and flow of helper T cells. They spent more than a year studying immune systems in healthy people and in 21 AIDS patients being treated at San Francisco General Hospital.

This produced what the authors described as the first direct clinical measurements of immune-system activity both in AIDS patients and an uninfected control group.

Results found no T-cell speed-up- and-collapse pattern in the infected people. What researchers found instead was that, along with reduced cell longevity, the virus caused slower cell production -- the opposite of what had been assumed to occur during this critical stage of the disease.

Just how the AIDS virus might damage T-cell production has yet to be unraveled. And there are as yet no proven therapies to address the new view of the disease, which would call for treatments that defend the immune system, insulating it from HIV or making it robust enough to withstand the virus. By comparison, today's therapies take direct aim at stopping the virus from reproducing.

AIDS experts emphasized that nothing in the study suggests people with HIV should change their current therapy, and certainly no one should stop taking anti-viral drug combinations now in widespread use.

But the experts said the new picture of the "dynamics" of the disease suggests new research priorities.

"No one had really done the study in humans to answer the true physiological questions of AIDS," said lead author Marc Hellerstein. "Is it mainly a disease of cell production or destruction? The answer can totally change your biological focus."

Dr. Paul Volberding, a veteran AIDS specialist at San Francisco General, called the new cell- tracking system at the heart of the study a "tremendously exciting" tool.

The method uses a harmless sugar molecule that can be easily detected in the DNA of the target cells, avoiding the health risks of radioactive or chemical markers in human test subjects.

"This gives us a tool we've been waiting for for a very long time," Volberding said.

Anthony Fauci, head of the infectious-disease branch of the National Institutes of Health and a noted AIDS expert, said the new study is drawing close scrutiny and could be widely influential -- if the results, which run counter to those from other well-respected laboratories, hold up.

"This is a controversial area," Fauci said. "I think it will remain a controversial area. It's a good paper, using an interesting technique . . . but the jury is still out."

An editorial in Nature Medicine portrayed the UCSF-Berkeley study as definitive evidence, but Ho indicated through a spokeswoman at the Aaron Diamond AIDS research center in New York that he is not yet convinced. Greene, by contrast, called the new study a "paradigm shift."

"This completely alters the way we think about the pathogenesis of AIDS," he said.

By all accounts, the AIDS virus infects and kills T cells. The argument is whether that's the main cause of fatal illness or if something else is at play.

"This study tells us HIV does two things," said UCSF researcher Joseph McCune. "It does destroy cells, but its main affect appears to be on the systems of cell production. What that tells us is that we have to get rid of the virus, no question about that, but we really need to focus our attention on the systems of cell production."

RETHINKING AIDS

New studies of HIV at work suggest a different view of how the virus can lead to a collapse of immune function in advanced AIDS. In the new view, the virus directly reduces the immune system's capacity for producing new disease-fighting T cells, rather than leading to an overactive system that ultimately exhausts itself:

Old view 1. Multiplying HIV particles infect T cells. 2. Immune system responds by cranking up production of new T cells in an effort to keep pace with the virus. 3. In the end stage of disease, the immune system collapses from exhaustion.

New view 1. HIV infects mature T cells, but not in sufficient numbers to explain how the disease progresses 2. Reseachers suspect that the virus may attack the immune system's cell-making capacity. 3. Final stage of disease caused primarily by collapse of immune system and reduced lifespan of T cells

HIV virus attacks T cell production system, probably in bone marrow and thymus.
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