The overall aim of the studies described in this application is to relate alterations in patterns of cytokine expression to the course of HIV infection and disease, by quantifying cytokine production in specific subpopulations of men in the Multicenter AIDS Cohort Study (MACS). In preliminary studies, cytokines that control immune function were found to be altered substantially in HIV infection. The proposed studies are to determine: (1) whether high levels of those cytokines fostering cell-mediated immunity (the TH1 cytokines, interferon-gamma [IFN-gamma] and interleukin-2 [IL-2], as well as IL-12, a cytokine that induces TH1 cells) are associated with relatively stable CD4 T-cell levels and with the absence of opportunistic infection (OI) in HIV infection; (2) whether the predominance of TH2 cytokines (IL-4 and IL-10) is associated with falling CD4 T-cell levels and with the occurrence of OI in HIV infection; (3) whether increases in tumor necrosis factor alpha (TNF-alpha) and IL-6 gene expression/levels are associated with an adverse disease course in the HIV-infected, and whether these cytokines are a better predictor of disease progression than the over-expression of TH-2 cytokines (IL-4 and IL-10); and (4) whether individual and complex changes in cytokine expression have relevance for prognosis (relative hazard) and whether these changes provide prognostic information not available from the measurement of CD4 T-cell number or serum activation markers (e.g., neopterin or beta-2 microglobulin). The subpopulations for study include these cohorts from the MACS: (a) HIV seroconverters; (b) HIV-seropositive men with different rates of decline of CD4 T-cell numbers; (c) HIV-positive men progressing to the acquired immunodeficiency syndrome (AIDS) within three years; (d) long-term HIV-positive survivors with little or no measurable loss of CD4 T-cells; (e) HIV-positive men who have had low CD4 numbers for an extended period of time without the occurrence of OI; and (f) a sample in which selected cytokines can be evaluated for relative hazard of AIDS occurrence. The researchers will measure: (1) serum levels of these cytokines; (2) levels of cytokine gene expression (mRNA) in peripheral blood mononuclear cells (PBMC's) by RNA polymerase chain reaction (PCR); and (3) cytokine production and levels of cytokine mRNA in response to in vitro stimulation of PBMC in the HIV-positive men and in HIV-negative men.
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