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The Search for an AIDS Cure Just Got Harder

Since 1981, when the first cases were reported, over 350,000 Americans have died of AIDS. Worldwide, over 5 million are affected, with numbers growing rapidly in India and Southeast Asia. The search for a cure has occupied researchers worldwide. Every few years a promising approach appears, only to disappoint. Starting in the mid-1990s, for example, researchers tried administering two drugs -- AZT and protease inhibitors -- together, and initial results were encouraging: widespread use of this combination therapy cut the U.S. death rate by almost two-thirds, from 43,000 AIDS deaths in 1995 to 31,000 in 1996, to just under 17,000 in 1997. Unfortunately, it turns out that this therapy only delays the onset of the disease, as the HIV virus is not eliminated from the body. When combination therapy is discontinued, virus levels in the bloodstream once again rise. Because of demanding therapy schedules, many side effects, and significant expense, long-term combination therapy does not offer a promising approach.

The most recent promising approach has involved vaccines made from live HIV viruses that have been weakened in a special way. To understand why this approach has excited doctors so much, it is necessary to go back to 1992, when Jennifer Learmont, a Red Cross official in Sidney, Australia, reported that an Australian man infected with HIV and eight people who had received HIV in transfusions of the man's donated blood (done before blood was routinely tested for HIV) did not seem to be developing AIDS. Fourteen years after being infected, all nine individuals were free of AIDS. When HIV virus isolated from these fortunate individuals was analyzed, the virus proved to be defective -- it lacked a tiny gene called nef, for "negative factor." This finding had the exciting implication that a live vaccine composed of the HIV strain with the defective nef gene might arm the human immune system against all strains of HIV, without endangering the person receiving the defective virus.

Initial tests of such a nef-negative defective live virus vaccine were carried out in monkeys. Researchers deleted the nef gene from the simian form of HIV, called SIV (for simian immunodeficiency virus), and injected it into laboratory monkeys. The initial results, first reported in 1992, were promising. Four treated monkeys were able to fend off infection completely from a virulent strain of the virus. As you can imagine, a clamor immediately arose for a full-scale test of a nef-negative live vaccine in humans. Caution by the F.D.A. was met with considerable criticism.

The caution proved justified. More extensive tests reported last February were not as encouraging as the initial studies. Three of sixteen treated monkeys came down with simian AIDS, not from the virulent test strain but from the vaccine itself -- the nef-negative vaccine was causing the very disease it was designed to prevent! "Our study indicates that it is not safe to conduct human tests of AIDS vaccines made from live, weakened viruses," the researchers warned. "There is a real risk of contracting AIDS from the vaccine itself."

Scientists were puzzled. If cutting the nef gene out of the HIV virus does not prevent the virus from causing AIDS in monkeys, then why didn't the Australians infected with HIV lacking nef get AIDS? Perhaps humans respond differently than monkeys. The hope remained that a human live vaccine might work.

Sadly, that hope has now been dampened. The Australian Blood Bank reports that the Australian infected with nef-negative AIDS 17 years ago has been recently diagnosed with an AIDS-related infection of the brain and spinal cord. Two of the recipients of his blood also now have signs of a weakened immune system. Of the other six, three are still healthy, and three have died from causes not related to HIV. In a similar discouraging development, an American infected with nef-negative HIV and AIDS-free for 15 years is also developing signs of AIDS. Researchers report that the man has experienced a sharp drop in his T cell count (the defensive cells of the immune system) to near the cutoff below which a person normally is said to have AIDS.

I have been lecturing to Washington University students about AIDS since 1982 -- for seventeen years -- and have watched many hopeful approaches fail when put to the test, as the nef-negative vaccine has now done. I tell my students not to focus on the single failed effort. A baseball game can be won without Mcguire hitting a home run. Instead we should focus on how much the failure teaches us. Every year we learn more about HIV and AIDS. A single here, a double there, the runs add up, and if we keep plugging away, we will most certainly prevail. That is how science works, chipping away at uncertainty until a clear path emerges. Knowing what doesn't work is one step closer to learning what does.

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