In two HIV-infected patients treated with potent combinations of anti-HIV drugs and interleukin-2 (IL-2), and in whom even highly sensitive tests could detect no viable HIV, the virus quickly rebounded to substantial levels when therapy was stopped, according to researchers at the National Institute of Allergy and Infectious Diseases (NIAID).
NIAID Director Anthony S. Fauci, M.D., chief of the NIAID Laboratory of Immunoregulation (LIR), Tae-Wook Chun, Ph.D., a section head within the LIR, and their colleagues report their data in the Oct. 28, 1999 issue of the journal Nature.
The new findings add to recent reports that suggest eradicating HIV from the body with currently available anti-HIV therapies is unlikely because the virus can hide in sanctuaries which drugs cannot access and can exist in a latent form on which drugs have no effect.
Scientists frequently refer to these sanctuaries, which are established very early in the course of HIV infection, as viral "reservoirs."
Reservoirs of HIV include certain immune system cells - notably resting (non-activated) CD4+ T cells of the blood and lymph nodes - and probably cells of the brain, gut, bone marrow, genital tract and other organs. These reservoirs, in which the virus continues to replicate at low levels even during aggressive treatment, are probable sources of the resurgent HIV seen when therapy is discontinued. The current study shows that at least one HIV reservoir - the pool of latently infected, resting CD4+ T cells - is itself rapidly replenished after therapy is discontinued.
"The persistence of HIV reservoirs poses a significant impediment to the long-term control of HIV infection and must be addressed by comprehensive approaches to the therapy of HIV-infected individuals," says Dr. Fauci. "Our research and that of other groups underscores the importance of developing more potent anti-HIV therapies, treatment strategies that specifically target the hiding places of HIV, as well as therapies that preserve and enhance HIV-specific immunity."
In the current report, the authors discuss two patients treated with highly active antiretroviral therapy (HAART - three or more anti-HIV drugs including a protease inhibitor) for 33 and 30 months, respectively. Both patients also had received intermittent intravenous infusions of IL-2 for 42 and 50 months, respectively. Before discontinuing therapy, both had levels of HIV in their plasma below 50 copies per milliliter of blood, the detection limit of the viral load assay used in the study. IL-2 is a regulatory protein of the immune system that has potent effects on the proliferation, differentiation and activity of CD4+ T cells and other immune system cells.
The researchers then used a sensitive culture technique to look for replication-competent HIV in the resting CD4+ T cells from the blood of these individuals and found none - even when they cultured up to 330 million cells from each individual. They then performed lymph node biopsies on the two patients and still could not isolate viable HIV.
"In these patients, we observed both a reduction of plasma virus to less than 50 copies per milliliter of blood and a marked diminution of an important viral reservoir - the pool of latently infected, resting CD4+ T cells," says Dr. Chun. "But the question still remained whether levels of HIV would remain low following discontinuation of therapy."
"The answer, unfortunately, was a resounding no," he adds. "When these patients discontinued HAART, virus was detected in the plasma of both individuals within three weeks, and the pool of resting CD4+ T cells carrying replication-competent HIV emerged shortly thereafter."
Dr. Chun adds: "Our data suggest that there may well be other HIV reservoirs in addition to resting CD4+ T cells which are responsible for the rebound in plasma viremia, a hypothesis that will be illuminated by further studies."
Co-authors of Drs. Chun and Fauci include Richard T. Davey, M.D., Delphine Engel, and H. Clifford Lane, M.D.
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.
TW Chun, RT Davey, D Engel, HC Lane and AS Fauci. Re-emergence of HIV after stopping therapy. Nature 401:874-75 (1999).
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