This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Nonpathogenic SIV infection in sooty mangabeys is characterized by a lack of increased immune activation and apoptosis during the chronic phase of infection. Since the early events following SIV infection are an important determinant of disease outcome, we investigated the kinetics of T lymphocyte apoptosis in four SIV negative sooty mangabeys and four rhesus macaques experimentally infected with a primary SIVsm isolate and six rhesus macaques infected with pathogenic SIVmac239. Peripheral blood mononuclear cells (PBMC) and lymph node lymphocytes were evaluated for apoptosis by flow cytometric measurement of intracellular activated caspase3. Apoptosis was measured both ex vivo immediately following lymphocyte isolation, and after overnight culture of lymphocytes in medium. Following SIV infection, a six- to 13-fold increase in ex vivo apoptosis of peripheral blood CD8+ T lymphocytes accounting for 2.7 percent to 5 percent of circulating CD8+ T lymphocytes was observed at two weeks in both mangabeys. This coincided with a three- to four-fold increase in proliferating Ki67+ CD8+ T lymphocytes as well as the appearance of a SIV-specific interferon-gamma ELISPOT response, suggesting that the apoptotic CD8+ T cells included a virus-specific component. Similar to sooty mangabeys, SIV infection in the rhesus macaques was associated with an eight to 13-fold increase in ex vivo apoptosis of peripheral CD8+ T cells. However in contrast to sooty mangabeys, the rhesus macaques also showed a nine to 24-fold increase in ex vivo apoptosis of peripheral CD4+ T cells at 2 weeks post infection. The presence of increased ex vivo apoptosis of CD8+, but not CD4+ T cells in sooty mangabeys suggests that decreased immune activation of CD4+ T cells early in SIV infection is an important determinant of disease outcome. Further understanding of the underlying mechanisms of differential CD4+ T cell apoptosis in sooty mangabeys and rhesus macaques could provide useful insight into AIDS pathogenesis.
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