Distinct SIV-specific CD8(+) T cells in the lymph node exhibit simultaneous effector and stem-like profiles and are associated with limited SIV persistence.

Human immunodeficiency virus (HIV) cure efforts are increasingly focused on harnessing CD8(+) T cell functions, which requires a deeper understanding of CD8(+) T cells promoting HIV control. Here we identifiy an antigen-responsive TOX(hi)TCF1(+)CD39(+)CD8(+) T cell population with high expression of inhibitory receptors and low expression of canonical cytolytic molecules. Transcriptional analysis of simian immunodeficiency virus (SIV)-specific CD8(+) T cells and proteomic analysis of purified CD8(+) T cell subsets identified TOX(hi)TCF1(+)CD39(+)CD8(+) T cells as intermediate effectors that retained stem-like features with a lineage relationship with terminal effector T cells. TOX(hi)TCF1(+)CD39(+)CD8(+) T cells were found at higher frequency than TCF1(-)CD39(+)CD8(+) T cells in follicular microenvironments and were preferentially located in proximity of SIV-RNA(+) cells. Their frequency was associated with reduced plasma viremia and lower SIV reservoir size. Highly similar TOX(hi)TCF1(+)CD39(+)CD8(+) T cells were detected in lymph nodes from antiretroviral therapy-naive and antiretroviral therapy-suppressed people living with HIV, suggesting this population of CD8(+) T cells contributes to limiting SIV and HIV persistence.