There is increasing evidence that chronic activation of the immune system may be a major factor leading to AIDS and paradoxically to its complete failure. From initial infection to late-stage HIV disease multiple signs of activation involving all lymphocyte subsets have been documented. To address problems associated with lentiviral disease, infection of macaques with the related simian immunodeficiency virus (SIV) is the most appropriate model system. Using a family of highly related SIV strains with defined biologic properties that induce a spectrum of disease in macaques, the investigators propose to identify: 1) signal transduction pathways activated in macaque lymphocytes after SIV infection; 2) the mechanism of apoptosis associated with SIV infection; 3) the roles of SIV Nef and Env proteins in cellular activation, apoptosis and disease progression; and 4) specific genes or regions of the SIV genome that influence viral pathogenesis during evolution of the quasispecies. A combination of in vitro and in vivo techniques, such as immunofluorescence, radioimmunoprecipitation, immunohistochemistry and in situ hybridization, to assess the expression of specific cellular genes during SIV infection will be used. Other studies include PCR-mediated analyses of mRNA expression of cellular proteins; transfection of cells with vectors expressing SIV Nef and Env proteins; sequence analysis of specific regions in SIV proviral DNA and genomic RNA in tissues obtained during persistent infection of macaques; evaluation of the effects of changes in regions of the SIV genome on pathogenesis. These studies will test the hypothesis that HIV/SIV and their antigens interfere with normal cellular signal transduction pathways, leading to uncontrolled immune system activation and ultimately to increased viral burden, pathogenicity, anergy and cell death.
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