Fauci: Host Factors Key to Control of HIV Infection
The body has potent mechanisms for containing HIV, including immune system cells called CD8+ T cells, that may be more effective than any antiretroviral drug in controlling HIV infection, says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID) and chief of the NIAID Laboratory of Immunoregulation (LIR). Recent LIR studies of these mechanisms--generically known as "host factors"--have provided researchers with potential new targets for therapeutic intervention.
Dr. Fauci will discuss "Host Factors in the Pathogenesis of HIV Disease" and his laboratory's recent findings on Monday, Jan. 30 at 8:30 a.m. at the Second National Conference on Human Retroviruses and Related Infections at the Sheraton Washington Hotel in Washington, D.C. Dr. Fauci also will participate in a press briefing at 11:30 a.m. at the hotel.
Recent studies of long-term non-progressors, HIV-infected individuals who show no decline in immune function for many years, demonstrate that certain immune responses can be very effective at containing the replication and spread of HIV," says Dr. Fauci. "The effectiveness of such factors is also observed in most other HIV-infected individuals in the weeks following infection with HIV, when the virus is contained to a large degree following its initial dissemination. Our laboratory has been working to delineate the host factors that slow the progression of HIV disease, with an eye toward their use as targets for therapies to augment antiretroviral drugs."
Dr. Fauci and his colleagues have recently focused on how cytokines (the signalling molecules of the immune system) and the interactions between various immune system cells induce the replication of HIV, and how such replication might be controlled.
The researchers have found that when dendritic cells, which present invaders to the immune system for processing, interact with CD4+ T cells in an HIV-infected individual, HIV replication increases.
In laboratory experiments, CD4+ T cells taken from HIV-infected individuals produced very little HIV, even when interleukin-2 (IL-2), a cytokine that can stimulate HIV replication, was added. However, when the investigators added dendritic cells taken from the same individual, significant amounts of virus were produced.
The normal cell-to-cell interactions that take place in the environment of the lymph node, where dendritic cells constantly come into contact with infected CD4+ T cells, probably result in the upregulation of HIV expression," says Dr. Fauci.
Dr. Fauci and his group also have provided new information on how CD8+ T cells may suppress virus replication. When the investigators cultured CD4+ T cells together with dendritic cells from an HIV-infected individual, they noted significant HIV replication, but when they added CD8+ T cells, HIV replication was largely blocked.
They also found that CD8+ T cells can block the cytokine signals that normally influence HIV replication. In a series of in vitro experiments, they added cytokines such as tumor necrosis factor, interleukin-1-beta or interleukin-6 (all of which can boost HIV replication in infected cells) to mononuclear cells of an HIV-infected individual and found little or no virus production. However, when CD8+ T cells were removed from the cell suspension, the same cytokines induced significant HIV replication. When CD8+ T cells were returned to the cell culture, virus replication was once again suppressed.
"Our data suggest CD8+ T cells are able to block both the cell-to-cell interactions and the cytokine signals that upregulate HIV expression," Dr. Fauci explains.
The researchers also have found that adding IL-2 to CD4+ T cells from HIV-infected individuals caused very little viral replication when CD8+ T cells were present. The reason for this, they demonstrated, is that IL-2 induced the suppressing function of CD8+ T cells, which overrode the cytokine's other effect of boosting viral replication in CD4+ T cells.
"Our studies show that IL-2 is a potent inducer of the suppressor phenomenon in CD8+ T cells, a function that supersedes its ability to induce virus production in CD4+ T cells," says Dr. Fauci.
In contrast, the researchers found that interleukin-12 (IL-12), a less potent inducer of viral replication in CD4+ T cells, did not significantly induce suppressing activity in CD8+ T cells, and induced production of virus to varying degrees.
"Taken together, our studies show that cytokines not only induce HIV expression in a complex manner, but they are also involved in the modulation of those host factors that control HIV expression, such as CD8+ T cells," says Dr. Fauci.
"These studies add to what we have learned from our studies of long-term non-progressors, a group of individuals who comprise an extraordinarily useful cohort for studying host factors," he adds.
As noted in the Jan. 26, 1995 issue of The New England Journal of Medicine by Dr. Fauci and others, studies of these individuals show that most have low-to-moderate levels of CD4+ T cell activation as well as significant CD8+ T cell suppressor activity.
"It is likely that long-term non-progressors are a heterogeneous group: some may be infected with a weakened virus, while others are examples of how host factors, in some circumstances, can contain HIV disease," says Dr. Fauci. "Since we know from studying long-term non- progressors that the immune system may be more powerful than any antiretroviral agent in containing the spread of virus over a long period of time, it makes sense to augment antiretroviral therapy with modulation of the immune system."
Toward this end, NIAID researchers have treated a small number of patients with intravenous infusions of IL-2, given for five consecutive days every two months over a period of two to three years, in addition to antiretroviral therapy. Preliminary results have been encouraging with significant and sustained rises in CD4+ T cell counts in the majority of individuals with CD4+ T cell counts greater than 200/mm3 of blood.
NIAID, a component of the National Institutes of Health, supports investigators and scientific studies at universities, medical schools, hospitals and research institutions in the United States and abroad aimed at preventing, diagnosing and treating such illnesses as AIDS, tuberculosis and asthma as well as allergies. NIH is an agency of the U.S. Public Health Service, part of the U.S. Department of Health and Human Services.