Leading HIV Researcher Identifies Molecular Mechanism That Enhances NaturalImmune Defense Against HIV Infection

April 19, 1998

SAN FRANCISCO -- Enthusiasm about the "cocktail" of drugs so successfully suppressing the advance of HIV in infected people has been shadowed recently by warnings from a leading HIV researcher at UC San Francisco that the drugs don't address the ultimate concern.

That concern, said UCSF's Jay Levy, MD, one of the discoverers of HIV and a leader in understanding its mechanisms, is the need to eradicate HIV from infected cells, so that these protected reservoirs of the virus will not be able to allow the emergence of drug-resistant strains. Current therapies simply prevent the spread of HIV to new cells.

To address the larger issue, said Levy, research should focus on what appears to be a natural immunity to the virus in some people. These infected individuals remain healthy for more than 15 years without any treatment. Being able to induce their type of immune response could ultimately lead to the development of a synthetic vaccine that could prevent the virus infection, Levy said.

Today, April 19, at the Federation of the American Society of Experimental Biology (FASEB) meeting here, Levy's colleagues Sharon Stranford, PhD, and Edward Barker, PhD, both postdoctoral fellows in Levy's laboratory, presented their latest findings not only on the molecular basis of this apparent natural immune response, but on a molecular mechanism that enhances it.

"This line of research holds some promise," said Levy, UCSF professor of medicine and director of the Tumor and AIDS Virus Research Laboratory. "I believe the present approach to controlling HIV is doomed to fail. There is no restoration of the immune system in the treated people and the virus will eventually become resistant to the drugs."

Already, Levy pointed out, several people on drug treatment have resumed production of high levels of drug-resistant virus.

"Unless anti-AIDS treatments also attack the infected cells, as could be initiated by a vaccine or immune therapies," he said, "we will see the return of a large number of AIDS cases and the transmission of drug-resistant viral strains."

In one study presented at FASEB, Levy and colleagues reported that the reason at least 80 people they studied did not become infected with HIV despite hundreds of exposures through sexual contact or IV drug sharing was because they had the unique immunological ability to marshal the response of CD8+ lymphocytes, a specialized group of infection-fighting white blood cells. (This finding, in research led by Stranford, in Levy's laboratory, was initially reported last month at the 10th National AIDS Update Conference in San Francisco).

In laboratory studies, Stranford showed that, as in the general population, the CD4+ lymphocytes of these people were susceptible to HIV infection. It was only in the presence of the CD8+ cells that viral replication was stopped. The CD8+ cells of non-HIV exposed individuals studied in the lab did not mount this response.

"We think this immunity results from exposure to low amounts of virus, which is enough to get the cellular immune antiviral response going," said Levy. "Each subsequent exposure then acts as a kind of booster." He said the researchers do not know why the CD8+ cell antiviral response occurs in some people and not in others.

In the second study from the Levy laboratory presented at FASEB, Barker identified a molecular link that is critical to enhancing this cell-mediated antiviral response. He and colleagues determined that when CD8+ cells were exposed to macrophages expressing a CD86 molecule on their surface, their antiviral action was amplified. Macrophages are another type of immune-system cell and play a role in increasing CD8+ cell function.

While this study was the first to show that macrophages are involved in this CD8+ and HIV response, the observation was not unexpected, as macrophages are known to be involved in cellular immune responses. But researchers had previously suspected that the macrophages stimulate CD8+ cells through the CD80 molecule, rather than the CD86 molecule.

"We've shown that the molecules on the surface of the macrophages play an important role in enhancing this response," said Barker, "and that the CD86 molecule is a critical factor."

The researchers demonstrated the role of the CD86 molecule through several procedures conducted in the laboratory: When they blocked the interaction of the CD28 molecule on CD8+ cells with the CD86 molecule found on macrophages, the macrophages' enhancing effects were abrogated. When they exposed macrophages to anti-CD86 antibodies, the CD8+ cells were not stimulated.

In contrast, anti-CD80 blocking antibodies had little effect on the ability of macrophages to enhance CD8+ cell antiviral response.

Finally, the researchers were able to reverse the decreased antiviral response that followed treatment of macrophages with anti-CD86 neutralizing antibodies by exposing the CD8+ cells to anti-CD28 antibodies, which are able to carry out the same function as the CD86 molecule.

"These studies indicate that engagement of the CD28 molecule on CD8+ cells with the CD86 molecule on macrophages is critical for optimal suppression of HIV replication by the CD8+ cells," said Levy.

"Further studies are needed to determine if the reduced CD8+ cell antiviral response associated with progression to AIDS can be due to a decreased CD86 expression on antigen presenting cells, such as macrophages. If it is, this information could provide a direction for developing a drug to prevent it."

University of California - San Francisco

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