AIDS studies suggest new directions, therapies.

AIDS studies suggest new directions, therapies

The variability of AIDS virus--fromits genes to its effect on people -- sometimes seems matched only by the diversity of approaches that can be taken toward its study. Three new reports suggest a variety of actions for the virus or for the body's reaction to it; each of the three could lead to new therapeutic tacks.

The reports detail a newfound importancefor immune system suppressor cells in controlling human immunodeficiency virus (HIV), a suggestion that the virus sparks an autoimmune attack, and the discovery of a small protein that blocks the virus's binding site on its target cells. How the three sets of findings mesh with one another remains to be seen.

Jay A. Levy and his colleagues at theUniversity of California at San Francisco came up with what is perhaps the most paradoxical finding of the three -- that suppressor immune cells, rather than effector cells that initiate and direct immunity, are key to fighting off HIV infection. Boosting suppressor cells could prevent or help counter infection, they suggest.

Levy and his colleagues studied theblood of three healthy homosexual men who had antibodies to HIV but from whom no HIV could be cultured. When the researchers grew the men's white blood cells in the laboratory and removed the suppressor cells, called CD8 cells, they found biochemical signs of the virus's presence. When they added the suppressor cells back to the culture, signs of the virus disappeared. They also found that a person's own suppressor cells protected his cells better than other people's, and that the more CD8 cells, the stronger the effect. They report on the results in the Dec. 19 SCIENCE.

That suppressor cells could hold incheck an immunosuppressive virus is not as counterintuitive as it sounds. Further experiments indicated that the CD8 cells may be releasing a factor that squelches replication of the virus, Levy and his colleagues report. The discovery also suggests an explanation for why some people infected by the virus don't develop the syndrome: It could be that their suppressor cells are more active.

Anthony Fauci, director of the NationalInstitute of Allergy and Infectious Diseases, commented in a prepared statement, "It's an interesting study of potential importance in understanding the mechanism of how the body defends itself against replication of HIV. We look forward to further studies confirming this observation and delineating the precise mechanism of the suppressive effect which was noted."

Levy says he'd like to try growing CD8cells from AIDS patients' blood samples and giving them back to the patients in higher doses, after he first determines the desired levels of suppressor cells. Too many suppressor cells could have a damaging effect. "We've got to be very careful before we go to clinical trials," he says. If all goes well, such trials could begin within the next six months, he estimates.

Meanwhile, other San Francisco researchershave come up with a theory for how the virus wreaks its havoc. According to John L. Ziegler of the Veterans Administration Medical Center and Daniel P. Stites, who was also an author of the CD8 study, HIV may cause the body to attack itself. While the idea of AIDS as an autoimmune disease has been proposed before, these researchers suggest a precise mechanism for how the virus could induce the attack.

The problem, they say in the DecemberCLINICAL IMMUNOLOGY AND IMMUNO-PATHOLOGY, could result from a similarity between the "hook" the virus uses to grab its target -- immune effector cells called CD4 or T4 cells -- and an unrelated protein on other white blood cell types that tells the immune system that these cells are "self" and shouldn't be rejected.

According to Ziegler and Stites's hypothesis,when an infected person makes antibodies to the HIV hook, these antibodies would also attach to the "self" areas of white blood cells, blocking their function or leading to their demise. The scientists' conclusion explains why, as observed in AIDS patients, the virus can infect only 0.01 to 0.1 percent of its CD4 cells yet still devastate the immune system.

The hypothesis also implies that immunesystem suppressants lik cyclosporine could prevent the deadly white blood cell loss. Cyclosporine has been tried by French researchers in AIDS patients (SN: 11/9/85, p.293), but the researchers have not yet published their results. There may be nothing left to restore by the time a person has AIDS, Ziegler says, but he and his colleagues are beginning a preliminary trial of cyclosporine in humans. They are also looking for the hypothesized antibody that reacts with HIV and with white blood cells.

The CD8 and autoimmune theories arenot mutually exclusive. "It could be," says Levy, "that the suppressor cell, by blocking the virus, would also prevent the production of autoantibodies." The autoantibodies could be a secondary effect that makes things worse, he suggests.

The third study, like the other two, hastreatment implications. Using a paradigm set up fo studying brain neuropeptides and their receptors, researchers found a short peptide on the HIV envelope protein that binds to brain cells in HIV infection. By adding just the peptide to a cell culture line, Candace B. Pert and Joanna M. Hill of the National Institute of Mental Health and several other government researchers were able to block entry of the whole virus, they report in the current PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (Vol. 83, No. 23). Analogs of the peptide also worked.

Pert's group plans to try injecting along-lasting analog of the peptide in humans with AIDS in early 1987. For people already infected, says Hill, the peptide could block infection of new cells. Though the peptide would be blocking a receptor that presumably has a function besides serving as the HIV attachment site, the researchers aren't expecting that the blockage will cause serious side effects and have seen none in animal trials.