This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tregs were initially defined as CD4+CD25+, suppress T-cell activation and proliferation in mice and humans. As chronic immune activation and rapid turnover of T cells are hallmarks of pathogenic HIV/SIVmac infections in humans and Rh, these cells may play an important role in HIV/SIV pathogenesis. Rh and AGMs are the best models for the study of SIV pathogenesis. They differ in one fundamental aspect: while Rh infected with SIVmac develop AIDS, AGMs infected with their species-specific SIVagm remain healthy for long periods of time. Our preliminary studies showed a loss of CD4+CD25+ T cells in SIVmac-infected Rh that may explain the aberrant chronic T cell hyperactivation described in this pathogenic infection. In contrast, we have found an increase in the number of Tregs during very early stages of SIVagm infection. To clearly define the role of Tregs in pathogenic and non-pathogenic SIV infections, we designed experiments in this project for normal, uninfected Rh and AGMs, to confirm the existence of functional Tregs and to verify our ability to manipulate this T cell subset. We first characterized Tregs in Rh and AGMs. As CD25 is not a specific marker for Tregs;we focused on identification of specific markers for Tregs such as FOXP3, GITR, CD127 and neuropilin-1 in association with previously studied CD4+CD25+ T cells. We also confirmed the existence of fully functional Tregs in non-human primates by determining the in vitro suppressive functions of CD4+CD25+ T cells. We determined the distribution of Tregs in tissues in Rh and AGMs. We showed that the majority of Tregs are present in blood and LNs and only few FOXP3 positive cells are located in the intestine. We also verified the capacity of available anti-CD25 blocking/depleting drugs to eliminate Tregs in Rh and AGMs in vitro and in vivo. Combined, these experiments were designed to characterize and manipulate simian Tregs in order to examine the role of these cells in AIDS pathogenesis.
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