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Human immunodeficiency virus (HIV) persistence during antiretroviral therapy (ART) is associated with heightened plasma interleukin-10 (IL-10) levels and PD-1 expression. We hypothesized that IL-10 and PD-1 blockade would lead to control of viral rebound following analytical treatment interruption (ATI). Twenty-eight ART-treated, simian immunodeficiency virus (SIV)mac 239 -infected rhesus macaques (RMs) were treated with anti-IL-10, anti-IL-10 plus anti-PD-1 (combo) or vehicle. ART was interrupted 12 weeks after introduction of immunotherapy. Durable control of viral rebound was observed in nine out of ten combo-treated RMs for >24 weeks post-ATI. Induction of inflammatory cytokines, proliferation of effector CD8 + T cells in lymph nodes and reduced expression of BCL-2 in CD4 + T cells pre-ATI predicted control of viral rebound. Twenty-four weeks post-ATI, lower viral load was associated with higher frequencies of memory T cells expressing TCF-1 and of SIV-specific CD4 + and CD8 + T cells in blood and lymph nodes of combo-treated RMs. These results map a path to achieve long-lasting control of HIV and/or SIV following discontinuation of ART., (© 2024. The Author(s).)

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., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)