The Perils of Discontinuing Therapy: Without HAART, Cytokines Stimulate HIV From Latently Infected Cells
When an HIV-infected patient discontinues highly active antiretroviral therapy (HAART), the virus almost invariably rebounds to substantial levels, even if virus had become undetectable by standard tests because of therapy. New findings from the National Institute of Allergy and Infectious Diseases (NIAID), reported in the July 6, 1998 Journal of Experimental Medicine, provide an explanation.
"Latently infected, resting CD4+ cells, although relatively few in number, may be the embers that re-ignite active HIV infection if a patient stops taking combination therapy, or if the drugs become ineffective," says the paper's lead author, Tae-Wook Chun, Ph.D., of the NIAID Laboratory of Immunoregulation (LIR). "Our new data suggest that the virus rapidly rebounds because of factors present in the normal environment of the lymph nodes, particularly cytokines, which stimulate these cells to produce virus."
HAART (potent combinations of HIV drugs, generally including a protease inhibitor) can reduce the amount of virus in a person's plasma to levels that are not detectable by the most sophisticated laboratory tests. Despite the powerful effects of these drugs, however, HIV is not completely eliminated from the bodies of persons taking them. Rather, the virus persists in safe havens where the immune system cannot detect it. These hiding places include non-dividing, resting CD4+ T cells in the blood and lymph nodes, which can harbor HIV DNA for prolonged periods while remaining invisible to the immune system. In an HIV-infected person's body, 1 to 10 of every million resting CD4+ T cells contain HIV that is capable of replicating.
Many scientists think that these viral sanctuaries pose the greatest challenge to the long-term control of HIV infection in patients receiving anti-HIV therapy.
The new data from the LIR buttress this view. In a series of in vitro experiments, Dr. Chun and his colleagues found that resting, latently infected CD4+ cells readily produced virus when bathed in stimulatory molecules found in the normal environment of the lymph node. If the drugs that comprise HAART were added to the cells, no virus was produced.
"Without HAART, we found that interleukin-6, tumor necrosis factor-alpha and interleukin-2, signalling molecules which are normally found in copious amounts in a person's lymph nodes, readily induced HIV replication in latently infected, resting CD4+ T cells," says Dr. Chun. "Our in vitro findings help explain the well-documented phenomenon of viral rebound seen in virtually all patients with no easily detectable virus in their blood as a result of HAART who discontinue therapy."
The researchers found that the cytokine combination activated purified resting CD4+ T cells from both HIV-infected patients receiving HAART, and from HIV-infected patients who had never taken HAART. Previous studies had shown that the three cytokines could independently induce HIV replication in cell lines, and in certain cells from the bloodstream. Before this study, however, the effects of the cytokines on latently infected, resting CD4+ T cells were unclear.
The new data suggest possible approaches to "purging" the body of cells latently infected with HIV.
"We now know that it is possible to drive latently infected CD4+ cells, at least in vitro, to a state of productive infection by using combinations of cytokines and/or antibodies to the CD3 molecule on the cell surface," says Anthony S. Fauci, M.D., NIAID Director, LIR Chief, and senior author on the paper. "Thus, one approach to purging these cells might be to stimulate them to spit out virus under the cover of HAART. Two assumptions are built into this scenario: cells activated to produce virus will die, and HAART will prevent the spread of released virus."
"Our group and others are pursuing further laboratory studies as well as clinical trials with HIV-infected patients to determine if such an approach is feasible."
Co-authors of Drs. Fauci and Chun include Delphine Engel, Stephanie B. Mizell and Linda Ehler.
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
Press releases, fact sheets and other NIAID-related materials are available on the Internet via the NIAID home page at http://www.niaid.nih.gov. The home page for the 12th World AIDS Conference is http://www.aids98.ch.
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