The quality of SIV-specific fCD8 T cells limits SIV RNA production in Tfh cells during antiretroviral therapy.

The attack and defense of infected cells and cytotoxic CD8 T cells occur in germinal centers in lymphoid tissue in chronic persistent HIV/SIV infection. Latently infected cells, the therapeutic target of HIV infection, accumulate in follicular helper T (Tfh) cells in lymphoid tissue; the impact of HIV-specific follicular CD8 (fCD8) T cells in lymphoid tissue on the latently infected cells remains unknown. We infected 15 cynomolgus macaques with SIVmac239 and examined the contribution of SIV-Gag-specific fCD8 T cells, defined by activation-induced markers (AIMs), to SIV-infected cells. Eight out of the 15 infected macaques served as progressors; a chronic phase combination antiretroviral therapy (cART) model was established for the eight macaques (progressors) with chronic persistent infection status, wherein cART was started in the chronic phase and discontinued after 27 weeks. Seven macaques that naturally controlled the viremia served as natural controllers. The frequency of SIV-Gag-specific fCD8 T cells was inversely correlated with the amount of cell-associated SIV- RNA in the Tfh only under cART or in the controllers but not in untreated progressors. scRNA-seq of SIV-Gag-specific fCD8 T cells in various conditions revealed that the gene expression pattern of SIV-Gag-specific fCD8 T cells in the controllers was closer to that of those under cART than the untreated progressors. Comparing the SIV-Gag-specific fCD8 T cells of those under cART to the controllers revealed their more exhausted and immunosenescent nature under cART. Improving the HIV/SIV-specific fCD8 T cells under cART by targeting those pathways might contribute to the development of potential curative strategies.IMPORTANCEWe infected cynomolgus macaques with SIVmac239 to establish an SIV-chronically infected cART model. We performed an in-depth characterization of Tfh and fCD8 T cells in three conditions-chronic stage of untreated, cART-treated, and natural controller cynomolgus macaques-by combining tissue section analysis and single-cell analyses of sorted cells. We revealed the inverse relationship between Tfh infection and SIV-Gag-specific fCD8 T cell frequencies as observed in HIV-infected individuals, thereby establishing the cynomolgus macaque as a relevant animal model to study the determinants of HIV/SIV persistence in lymphoid tissue. Additionally, scRNA-seq analysis of SIV-Gag-specific fCD8 T cells revealed an enrichment of exhausted or senescent transcriptomic signatures under cART. These data will provide the basic insights into virus-host CD8 T cell interactions, particularly within the follicular region, during latent HIV infection under ART.