In the absence of treatment, infection of rhesus macaques with pathogenic SlV, like HIV infection of humans, is almost always progressive with deterioration of immune function, and ultimately death due to either direct consequences of SlV itself or opportunistic infection. The tempo of progression, however, varies considerably from host to host, even with cloned virus, suggesting that host factors play a role in supporting and/or mitigating the extent and consequences of viral replication. Recent documentation of massive, systemic depletion of SlV """"""""target"""""""" cells (CCR5+, CD4+ memory T cells) in early SlVmac239 infection, and a concomitant, profound increase in the production and turnover of this population suggests that target cell availability and mechanisms of target cell generation may significantly contribute to the outcome of infection. Indeed, our preliminary data suggest that plateau-phase viral replication may be largely supported by infection of """"""""new"""""""" T cell targets generated by this marked increase CD4+ memory T cell turnover. The overall goal of this project is therefore to characterize the nature and regulation of T cell turnover in various stages of SlV infection, and to ascertain the impact of this regulation on viral dynamics and disease progression. Specifically, we will: 1) characterize depletion of pre-existent CD4+ memory T cell """"""""targets"""""""", and the extent, kinetics, anatomic location, infection rate, and fate of newly generated """"""""targets"""""""" over the course of SlV infection, and determine the relationship of these dynamics to systemic viral replication, CD8+ T cell dynamics, and long-term maintenance of CD4+ memory T cell numbers, 2) examine the effect of anti-retroviral therapy (ART), ART interruption, and cycled structured treatment interruptions on CD4+ memory T cell population dynamics and """"""""target"""""""" cell availability, 3) determine the extent to which SIV-specific responses, other Ag-specific responses, or """"""""bystander"""""""" (cytokine-driven) proliferation contribute to CD4+ memory T cell dynamics and target generation, and 4) ascertain whether T cell selective anti-proliferative therapy can inhibit overall CD4+ memory T cell turnover, alter viral target availability, and thereby influence viral dynamics and disease progression in either acute- and/or plateau-phase SlV infection.
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