AIDS researchers seeing their quarry in new light Discoveries shift focus from virus to immune system

September 07, 1993|By Newsday

After a long period of dismal results, AIDS research may finally be on a fruitful path, enlightened by a rapid-fire series of discoveries in recent weeks about the way the virus plunges the body's immune system into chaos, many prominent scientists say.

"It's like St. Paul seeing the light on the road to Damascus," declared a happily agitated Cecil Fox, a cellular biologist who is president of Molecular Histology Laboratories Inc. in Gaithersburg, Md.

"The history of this disease is a history of doorways never opened," said Dr. Joseph Sonnabend of the New York City-based Community Research Initiative on AIDS. "Finally, we are beginning to open the right doors."

Until recently, most research has focused on the human immunodeficiency virus, or HIV, and its ability to harm a component of the human immune system, called CD4 cells. But now a consensus is emerging that, from the earliest moments of infection, HIV tricks the immune system, setting it on a path of self-destruction that may continue even if the virus is eliminated. The damage, many scientists say, is done not directly by the virus but by an immune system that goes haywire, attacking itself and other parts of the body.

"It's clear you need the virus at some point to kick off the pathological events," said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. "But even if you knocked off the virus early you could still have damage to the immune system."

Even Dr. Robert Gallo, a top researcher at the National Cancer Institute whose own work has focused on the virus, now thinks most damage is not directly done by HIV.

"The molecular mimicry in which HIV imitates components of the immune system sets events into motion that may be able to proceed in the absence of further whole virus," Dr. Gallo said.

Many pieces of the puzzle remain obscure, many details of the process are hotly disputed, and many scientists, like Dr. Fauci, are far more guarded in their optimism than Mr. Fox and Dr. Sonnabend. But at a recent meeting of 500 AIDS scientists from around the world, it was clear that researchers separated by seas and languages are reaching new and strikingly similar conclusions about the way HIV causes disease and about the possible new directions for treatments.

Jacques Leibowitch of the Raymond Poincare Hospital in Garches, France, was among the most enthusiastic of those who gathered for the eight-day annual AIDS meeting, convened by Dr. Gallo in Bethesda, Md.

"It's bizarre, no? But at last we are getting some place. We started all our work on the wrong foot, because we were all focused on the bias of the discovery of the virus."

But now, he said, scientists are focused on how the immune system gets burned out.

"That's AIDS," he said. "The virus is benign in comparison to the enormous destructive activity of the immune system itself. Now the whole strategy is different."

Up to now, most research into acquired immune deficiency syndrome treatment has had one of two goals: trying to block reproduction of the AIDS virus, as with the anti-viral drugs AZT, ddI and ddC; or preventing and treating the opportunistic infections, such as pneumonia, that kill most people with AIDS once their immune systems are weakened.

Jolting the system

But if immune system self-destruction does turn out to be the key to AIDS, it seems logical that a severe jolt to the immune system early in HIV infection might set the system back on a proper course before the first opportunistic infections occur, many scientists now say.

Research on animals and on human cells suggest several possible "jolts," including:

* Total shutdown of the immune system, followed by a quick switch back on. In mice and monkeys, good results have followed temporary destruction of the immune system with radiation. Immune-suppressive drugs like cyclosporine and thalidomide might be similarly useful, and clinical trials of both agents are under way in the United States. A major problem, however, is that nobody yet knows how to reconstitute the immune system after it has been shut down.

* Stimulation of a sharp allergylike response with such things as poison ivy, small bits of tissue extracted from another person, or other irritants. In theory, this would hyperstimulate a response of the immune system's T cells that would counter the self-destructive one started by HIV. There is anecdotal evidence that people with family histories of allergies and asthma survive longer with HIV infection. So far, nobody has tried such hyperstimulation in clinical trials.

* Counter the destructive action of chemicals, called cytokines, that are the weapons in the immune system's self-destruction. Cytokines send a variety of signals throughout the immune system, and in the case of AIDS those signals are incorrect. This can prevent the body from absorbing food, send fevers soaring and shut down immune system responses to certain infections. Injection of "good cytokines" might counter the "bad cytokines" pumping through the bodies of people with HIV.

Easy to test

Mr. Fox, Dr. Fauci and microbiologist Ashley Haase of the University of Minnesota all say the most exciting thing about this juncture in the fight against AIDS is that every aspect of the new theory could be easily proven or disproved.

"Every aspect of this is testable," Mr. Fox says. "All we need is [someone tough] in charge [of coordinating research efforts]. Somebody who has the guts to do what needs to be done to get an answer. And we could have an answer within two years."

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