Dual role of circulating and mucosal Vd1 T cells in the control of and contribution to persistent HIV-1 infection

Curative strategies for human immunodeficiency virus (HIV-1) infection are hindered by incomplete characterization of the latent reservoir and limited enhancement of anti-HIV immune responses. In this study, we identified a novel dual role for peripheral and tissue-resident Vd1 T cells within the gastrointestinal mucosa of virally suppressed people with HIV. Phenotypic analyses identified an increased frequency of highly differentiated, cytotoxic effector Vd1 T cells that exerted potent inhibition of HIV-1 replication in vitro coinciding with direct increases in cytolytic function. Conversely, we detected an enrichment of HIV-1 DNA in tissue-resident CD4+Vd1 T cells in situ. Despite low CD4 expression, we found circulating Vd1 T cells also contained HIV-1 DNA which was replication-competent. We show that TCR-mediated activation of peripheral Vd1 T cells induced de novo upregulation of CD4 providing a plausible mechanism for increased permissibility to infection. These findings highlight juxtaposing roles for Vd1 T cells in HIV-1 persistence including significant contribution to tissue reservoirs. Human Vd1 T cells were FACS-purified ex vivo from PBMCs isolated from three ART-suppressed people living with HIV and three HIV-seronegative donors and interrogated by ATAC-seq.