Soon after the human immunodeficiency virus (HIV) enters a person's body, the virus sets up shop in resting (non-dividing) CD4+ T cells, according to researchers at the National Institute of Allergy and Infectious Disease(NIAID).
The pool of latently infected immune system cells is established even if a patient is treated soon after acute infection with powerful antiretroviral drugs that reduce plasma levels of virus to extremely low or undetectable levels. Within the safe havens of resting CD4+ T cells, the virus may persist for years, despite highly active antiretroviral therapy (HAART), which is generally a combination of three drugs, including a protease inhibitor.
Latent reservoirs of HIV, including resting CD4+ T cells, present a formidable obstacle to the ultimate control and possible eradication of HIV from an infected person's body," says Tae-Wook Chun, Ph.D., an investigator in NIAID's Laboratory of Immunoregulation (LIR). Adds LIR Chief and NIAID Director Anthony S. Fauci, M.D., "Latently infected CD4+ T cells are potential sources of new viral replication if a patient stops therapy or is unable to adhere to the proper treatment regimen. We now know that these reservoirs are established very early in the course of infection." Dr. Fauci notes that "the establishment of the pool of latently infected, resting CD4+ T cells appears to occur around the time of the initial burst of virus replication seen in most patients with acute HIV infection. "Drs. Chun, Fauci and colleagues report their latest findings in the July 21, 1998, issue of the Proceedings of the National Academy of Sciences.
The investigators studied blood samples from 10 patients who were treated with the drugs zidovudine (AZT), lamivudin(3TC) and Crixivan (indinavir), soon after infection with HIV. Treatment was initiated between 10 days and 4.4 months following the initial onset of HIV-related symptoms. All of the patients responded positively to therapy, including five whose viral load fell to undetectable levels.
The LIR team found evidence of latently infected, resting CD4+ T cells in all 10 patients, even in an individual who had started HAART 10 days after the onset of the symptoms of acute HIV infection. Interestingly, the researchers found that neither duration of therapy nor the speed with which therapy was initiated correlated with the number of infected resting CD4+ T cells in a patient's blood. However, "The longest duration of therapy was 17 months, and it remains possible that an even longer duration of therapy with HAART, especially if initiated early in infection, may result in pronounced decreases in the pool of latently infected, resting CD4+ T cells," says Dr. Chun. "A smaller pool of latently infected cells would be more likely to ultimately be controlled by the immune defenses of the patient," adds Dr. Fauci.
The NIAID investigators and others are pursuing studies to identify people recently exposed to HIV and to treat them before the viral burst, which probably disseminates the virus widely throughout the body. Such studies will help determine whether it is possible to prevent the early establishment of pools of latently infected, resting CD4+ T cells.
There are a number of potential approaches to containing or depleting reservoirs of latently infected, resting CD4+ T cells that have already been established in HIV-infected individuals. At the recent World AIDS Conference in Geneva, Dr. Fauci presented three possibilities: maintaining a strong immune system; enhancing a weakened immune system; and developing methods to deliberately purge the reservoirs by activating the resting cells to produce virus under the cover of HAART. Dr. Fauci's Geneva lecture is available on the World Wide Web at http://webcast.aids98.org (see plenary sessions for June 30, 1998). Co-authors of Drs. Chun and Fauci include Delphine Engel of the LIR, and Drs. Lawrence Corey, M. Michelle Berrey and Theresa Shea of the University of Washington in Seattle.
Chun T-W, et al. Early establishment of a pool of latently infected, resting CD4+ T cells during primary HIV-1 infection. Proc Natl Acad Sci USA 1998;95(15):8869-73.
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