Noted UCSF researcher to argue innate immune system plays vital role in fighting HIV

July 06, 2000

A debate between leading AIDS researchers on the role of the immune system in HIV infection will highlight the plenary sessions at the upcoming XIII International AIDS Conference in Durban, South Africa (July 9-14). Titled "The Innate Immunity is as Important as the Adaptive Immunity in Preventing HIV Infection and Progression to Disease," the debate is scheduled for Monday, July 10 from 4:30 to 6:00 pm (Durban time) at the International Conference Center.

Jay Levy, MD, a professor of medicine at the University of California, San Francisco and one of the first to discover HIV, will argue for the proposition. At UCSF, Levy also is director of the Laboratory for Tumor and AIDS Virus Research.

The following background information covers the main points that Levy plans to emphasize in the debate. ---------------------------------------------------------------------------------------------------------------------------------------

The innate immune system consists of a variety of immune responses that are the first line of defense against the invasion of a pathogen. These responses occur within the first few hours or days of infection before adaptive immune responses are induced. Unlike the adaptive immune system, the innate system is not antigen specific. In addition, it does not create immune responses that have a memory of the pathogen that instigated the immune response.

Levy contends that many more persons would have been infected with HIV if the innate immune system had not been functioning. Moreover, the innate immune system helps prevent the onset of opportunistic infections and cancer. According to Levy, natural circulating substances in the blood can bind and inactivate HIV, and two major areas of the immune systems are involved in an innate response.

One area is interferon-producing cells (IPCs). Interferon is a protein produced by body cells. It fights viral infections and certain cancers. IPCs are, in principle, the major source for the release of interferon. Interferon arms the immune system to recognize the arrival of a pathogen and helps natural killer cells do their job. Those cells are a type of white blood cell that attacks infected body cells and cancer cells by binding to them and releasing lethal chemicals.

Generally IPC levels drop when CD4 cell numbers decrease. Levy, however, is familiar with two HIV patients with fewer than 50 CD4 cells, the infection-fighting white blood cells that are the natural target for HIV. The standard CD4 range among healthy individuals is between 400 and 1200, and fewer than 200 is an indication of full-blown AIDS. Of these two patients, one has fewer than four CD4 cells. Neither is on therapy with antiretroviral drugs or with prophylactic treatment for bacteria and parasites. These two individuals have not had an opportunistic infection or cancer. They have had low CD4s for at least 5 years. However, their IPCs have remained at normal levels. It appears that this component of the innate immune system is functioning to control HIV disease, and these cases show that people can have very few CD4 cells and still avoid opportunistic infections and cancer, according to Levy. IPCs typically start disappearing when CD4 cells drop below 250. By the time an individual advances to full-blown AIDS, the IPCs are usually wiped out. A study by Frederick Siegal, MD, medical director of the Comprehensive HIV Center and chief of the Section of HIV Medicine, St. Vincent's Hospital, New York City, who first described these cells, shows that after antiretroviral treatment, the return of CD4 cells is almost mirrored by the return of IPCs, Levy points out, calling this fortunate news.

The assumption is that IPCs, a vital part of the innate immune system, can hold opportunistic infections and cancer at bay. It is important to remember that HIV itself does not kill people, but rather the onslaught of opportunistic infections and cancer unleashed by HIV, he adds.

The second area concerns CD8 suppressor lymphocytes, a specialized group of infection fighting white blood cells, which Levy argues are actually part of the innate immune system.

The antiviral response of CD8 cells occurs early in primary (or acute) infection and can be noted before HIV specific antibody production is detected. CD8 suppressor lymphocytes respond to all strains of HIV as well as the simian AIDS virus; they are not virus specific. Moreover, they are noncytotoxic, meaning that they do not kill the CD4 cells that are infected with HIV. These are contrasted with other CD8 cells: the CD8 cytotoxic lymphocytes that are part of the adaptive immune system, are virus protein-specific, and directly destroy the infected cells. Most HIV-infected individuals develop a relatively strong virus-specific CD8 cytotoxic lymphocyte response, according to Levy, and unfortunately, this reaction by the adaptive immune system may also knock out normal CD4 cells and cause other toxic effects in the infected person.

In a study he conducted in 1997, Levy found that some people have a natural ability to protect themselves against HIV infection. Despite multiple exposure to the virus, these individuals have the unique ability to marshal CD8 suppressor lymphocytes to block replication of HIV. The CD8 antiretroviral response is mediated by a CD8 antiviral factor (CAF), a protein first described by Levy's group in 1989. The ability of CD8 suppressor lymphocytes to produce CAF and inhibit HIV replication is highest in infected individuals who are asymptomatic and decreases in people as HIV disease progresses. CAF thus resembles other cellular products of the body (e.g. interferons) that are naturally produced in response to virus infection.

These two areas of the innate immune system have, in some individuals, been effective defense mechanisms against HIV, especially in the very first stages of infection, Levy notes, and therefore highlight the possibility of alternative vaccine and treatment strategies.
-end-


University of California - San Francisco

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