Human Immunodeficiency virus (HIV) infection is characterized by a progressive loss of immune function that puts patients at risk for opportunistic infections and neoplasms. This loss of immune function is characterized by decreases in the numbers of circulating total, naive and memory CD4+ cells. The mechanisms for this profound cell loss remain incompletely understood. Highly active antiretroviral therapy (HAART) produces dramatic decreases in plasma HIV-1 RNA levels. HAART is associated with marked decreases in the incidence of opportunistic infections and mortality. It has been shown that the most significant factor associated with decreases in the incidence of new opportunistic infections is the immunologic response to antiretroviral therapy, as measured by CD4+ cell counts. Patients who do not experience CD4+ cell increases or who experience blunted increases remain at risk for these infections. A variable proportion of patients who attain plasma HIV-RNA levels below the limits of detection of currently available assays do not experience significant increases in CD4+ cell counts and remain at increased risk for these infections. It is not known why certain patients experience this virologic and immunologic dissociation. A non-radioactive method to measure CD4+ cell proliferation using deuterated glucose has been described recently. The early increases in CD4+ cells after initiation of HAART appear to be due to increased CD4+ cell proliferation, but whether differential CD4+ cell proliferation accounts for differential increases in CD4+ cells after initiation of HAART is unknown.
The Specific Aims are: 1) To ascertain whether demographic characteristics are associated with differential increases in CD4+ cells after initiation of HAART. We will compare demographic characteristics (namely age and sex) of patients experiencing marked increases in CD4+ cells after one year of effective HAART to those of patients not experiencing these increases. This analysis will help us ascertain whether non-modifiable host factors are associated with differential increases in CD4+ cells after HAART. 2) To ascertain whether immunological characteristics are associated with differential CD4+ cell increases after HAART. We will compare extensive flow cytometric panels that include markers of immune activation between patients experiencing and not experiencing CD4+ cell rises after one year of effective HAART. We will also compare spontaneous lymphocyte apoptosis, thymic size as measured by computerized tomographic scan, and recent thymic emigrants as measured by T-cell receptor excision circles between patients who exhibit and do not exhibit a virologic-immunologic dissociation after HAART. 3) To ascertain whether cell proliferation characteristics are associated with differential CD4+ cell increases after HAART. We will compare cell proliferation, as measured by incorporation of deuterated glucose, between patients experiencing and not experiencing CD4+ cell increases after HAART. This analysis will allow us to ascertain whether differential cell proliferation accounts for the virologic-immunologic dissociation. Twenty patients who have been receiving HAART for at least one year and have plasma HIV-RNA levels below the limit of detection for at least 8 months will be eligible to participate. Controls will be patients who have been receiving HAART for at least one year and who have experienced a CD4+ cell rise of at least 200 cells/microliter. Cases and controls will be matched for baseline CD4+ cell counts and plasma HIV-RNA levels. Demographic variables will be obtained from the patients' medical records. Various immunologic studies will be performed. Cell proliferation will be measured 7 and 14 days after the infusion of 100-grs of deuterated glucose by the method described by Macallan.
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