The proposal is a response to Program AnnounCement 96-060, Acute Infection and Early Disease Research Network We propose to recruit 30-50 individuals, primarily injection drug users, with recent HIV- l infection for detailed studies of the effect of early, aggressive treatment of HIV-1 infection. The treatments that will be given include newly developed, highly potent antiretroviral drug combinations; study participants will be randomized to receive or not receive the immunostimulatory cytokine, interleukin-2 (IL-2). The effect of these treatments on the natural history and pathogenesis of HIV-1 infection will be studied. Hypotheses to be tested include l) antiretroviral therapy will suppress, but not eradicate, infectious and latent HIV in PBMC; 2) the extent of suppression of HIV-1 will correlate with the fitness of the early HIV-1 isolate, and with the resiStanCe of the virus to drug therapy; 3) IL-2 will enhance the degree of viral suppression and will augment HIV-specific CLT memory pools; 4) suppression of HIV replication by the drugs will correlate with establishment of in vitro resistance of PBMC to infection with HIV; 5) IL-2 reduces the extent of HIV-l acute damage to the T Cell repertoire and accelerates the recovery from this damage, which is reflected in depletion of memory Cells and development of """"""""holes"""""""" in the T Cell repertoire; and 6) production of IL-12, a key stimulater of all- mediated immunity, is defective from the onset of HIV infection, and this defect is mediated by a complement-CD46 interaction on mononuclear phagocytes. These hypotheses will be tested in an integrated design using several newly developed methods for assessing latent infection of cells with HIV-1, diversity of T Cell receptor expression, phenotypic expression of CD4+ lymphocytes, viral fitness, and cytokine levels in vivo and in vitro. The data obtained will help define the optimal use of the new, potent therapies for HIV-1 infection, and will also help to understand the mechanism of immune system damage in HIV-l infection.
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