In the last number of months, dramatic improvements in the clinical course of HIV-1 infection have been documented in patients who are treated with combined antiviral drug therapy and includes a protease inhibitor and nucleoside inhibitors. Approximately 85% of many patients in several studies show a 2-3 log decrease in HIV-1 plasma load, and significant increases in CD4 T-cell numbers in the absence of clinical AIDS for at least one year on therapy. Based on the preliminary results in a trial with Indinavir (Merck 035), potent antiviral therapy for one year results in only partial recovery of anti-HIV-1 cytotoxic T-lymphocyte (CTL) immunity that is selective for certain viral proteins. T-cell recognition responses to HIV-1 and non-HIV-1 antigens are not fully reconstituted. Because T-cell immunity may be a major correlate of protection in HIV-1 infection, the efficacy of antireroviral drug therapy may in part depend on restoration of complete anti-HIV-1 CD8+ CTL and CD4+ T helper cell responses. The PI hypotheses that such restoration can be achieved with therapy by targeting host dendritic cells (DC) with certain forms of HIV-1 antigens that will activate naive T-cells and expand memory CTL and T-helper cells with HIV-1-specificity.
The specific aims of this proposal are to: (1) define the HIV-1-specific CD8+ and CD4+ T-cell responses pre- and post-combined therapy, including HIV-1 epitope delineation, T-cell phenotyping and T-cell receptor repertoire; (2) to determine the efficacy of DC-antigen delivery systems for HIV-1 proteins and genes for optimal in vitro stimulation of primary CD4+ and CD8+ T-cell responses in HIV-1-naive subjects; (3) restore and enhance HIV-1-specific responses of CD4+ T helper cells and CD8+ CTL in vitro, using DC-based antigen delivery systems in HIV-1-infected patients who have a partial, limited immunological response after treatment with combined antiretrovirals.
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