A Delicate Balance: Levels of HIV Replication are Strongly Influenced by Interaction of Positive and Negative Host Factors
New findings from the National Institute of Allergy and Infectious Diseases (NIAID) illuminate how the replication of the AIDS virus is tightly controlled by the interplay of positive and negative host factors. When in balance, these factors may keep the replication of HIV at a persistently low level, often for years, in people infected with the virus. Disrupting the delicate balance, however, can result in a dramatic increase in HIV replication, heralding the onset of the serious manifestations of HIV disease.
"Our studies explore the interactions of cytokines -- signalling molecules secreted by white blood cells -- some of which boost HIV replication and some of which are suppressive," says Anthony S. Fauci, M.D., NIAID director and chief of the NIAID Laboratory of Immunoregulation (LIR). "The new data underscore the importance of the body's own defense mechanisms to the HIV disease process, provide new insights into the pathogenic mechanisms of HIV, and suggest potential new targets for therapies."
Dr. Fauci will present his laboratory's recent findings in a lecture at the XIth International Conference on AIDS in Vancouver, British Columbia, on Tuesday, July 9 at 1:30 p.m. Pacific Time.
When a person is infected with HIV, the virus replicates rapidly during the first few weeks of infection and disseminates throughout the body, especially to the lymph nodes and related organs. The body's immune system fights back with killer T cells (CD8+ T cells) and antibodies, which dramatically reduce HIV levels. A person then may remain free of HIV-related symptoms for ten years or more, despite continuous replication of HIV.
Researchers know that a number of factors can boost HIV replication during the course of HIV infection. Dr. Fauci's group and others have shown that other infections, such as M. tuberculosis, as well as immunizations, activate immune system cells and increase production of virus in HIV-infected people. Chronic immune activation due to persistent infections, or the cumulative effect of multiple episodes of immune activation and bursts of virus production, likely contribute to the progression of HIV disease.
LIR scientists have demonstrated that certain cytokines normally secreted by a person's own immune cells can boost HIV replication. In experiments, ongoing for the past ten years, Dr. Fauci and his colleagues have shown that these inductive cytokines normally involved in inflammatory responses, such as tumor necrosis factor-alpha (TNF-), interleukin-1beta (IL-1-ß) and interleukin-6 (IL-6), can upregulate the virus. Whereas HIV actively replicates in cultures of immune cells taken from HIV-infected people, the addition of antibodies that block TNF-, IL-1ß and IL-6, which are produced by the cells in culture, shuts down HIV replication.
Recently, the investigators have shown that naturally occurring suppressive cytokines such as interleukin-4 (IL-4), interleukin-10 (IL-10) and transforming growth factor-ß (TGF-ß) can block the inductive cytokines in cell culture, thereby stopping HIV replication. IL-10, for instance, apparently stops HIV replication by blocking the activity of TNF- and IL-6.
Taking these experiments a step further, the researchers studied the immune cells of normal volunteers who were given either a placebo injection or an injection of IL-10. Following placebo injections, the cells of the normal volunteers were easily infected with HIV in the test tube, and made large amounts of TNF-. The cells drawn from volunteers given IL-10, however, lost their ability to make TNF-, and resisted infection by HIV for up to 48 hours.
In additional studies, the NIAID investigators administered a single, low dose of IL-10 to HIV-infected people and observed a marked, but quite transient, decrease in plasma viremia that lasted for several hours. Levels of virus returned to baseline at 24 hours following IL-10 infusion.
"Taken together, these experiments demonstrate that HIV replication is regulated by a delicate balance among the body's own cytokines, and that by altering this balance, you can dramatically influence the replication of the virus in the test tube and potentially even in the body," says Dr. Fauci.
Dr. Fauci also will discuss new data on the so-called "suppressor phenomenon" associated with CD8+ T cells, originally described by Dr. Jay Levy. In addition to killing HIV-infected cells directly by a process called cytolysis, these cells also secrete soluble factors that suppress HIV replication in both blood and lymph nodes taken from HIV-infected people.
Part of the CD8 suppressor phenomenon appears to be due to the secretion by CD8+ T cells of signalling molecules called beta-chemokines, which normally recruit inflammatory cells to the site of an infection. Three of these molecules -- RANTES, MIP-1 and MIP-1ß -- apparently block HIV replication by occupying receptors necessary for the entry of macrophage-tropic strains of HIV into their target cells.
Although it was initially thought that the effects of these three chemokines fully explained the CD8 suppressor phenomenon, Dr. Fauci and his group have shown that not all non-cytolytic suppression of HIV by CD8+ T cells can be explained by the three factors. In HIV-infected cells cultured with CD8+ cells, the investigators found that HIV remained suppressed even after they blocked RANTES, MIP-1 and MIP-1ß with antibodies.
"The CD8 suppressor phenomenon cannot be completely explained by beta-chemokines," says Dr. Fauci. "Clearly, there is another CD8-derived suppressor factor(s) that has not yet been identified."
Dr. Fauci's principal collaborators in these experiments include: Drs. Drew Weissman, Audrey Kinter, Delia Goletti and Andrea Rubbert.
NIAID is a component of the National Institutes of Health(NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as AIDS and other sexually transmitted diseases, tuberculosis, asthma and allergies. NIH is an agency of the U.S. Public Health Service, U.S. Department of Health and Human Services.