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. Virus-specific CD4+ T lymphocytes are likely to play a central role in initiating and maintaining antiviral immunity. Investigation of these responses in macaques infected with SIV strains offers an excellent opportunity to better understand the relationship of these responses to disease progression and protective immunity. We investigated SIV-specific CD4+ T cell responses in rhesus macaques chronically infected with attenuated or pathogenic SIV strains. Analysis of SIVdeltanef-infected animals revealed a relatively high frequency SIV-specific CD4+T response representing 4 percent-10 percent of all CD4+ T lymphocytes that was directed against multiple SIV proteins. Gag-specific CD4+T cell responses in wild-type SIV-infected animals were detected at a 5 to 10-fold lower frequency than in SIVdeltanef-vaccinated animals and were inversely correlated with the level of plasma viremia. Phenotypic analysis revealed that SIV-specific CD4+ cells from deltanef-infected animals were predominantly CD28- CCR7- and CCR5-, consistent with an intermediate differentiation stage, but also included a fully differentiated CD45RA+CCR7- subset. In contrast, SIV-specific CD4+ T cells from SIV-infected animals were mostly CD28+ CCR7+ and CCR5+, consistent with an early to intermediate differentiation stage. The CD45RA+CCR7-CD4+ subset from deltanef-infected animals was highly enriched for effector CD4+T cells, as evidenced by expression of perforin and upregulation of the lysosomal membrane protein CD107a following stimulation with Gag peptides. The ability of SIVdeltanef to induce a high-frequency virus-specific CD4+T cell response with direct effector function may play a key role in protective immunity produced by vaccination with attenuated SIV strains.
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