We compare the transcriptomics of circulating follicular (CXCR5+) CD8 T cells to the conventional (CXCR5-) CD8 T cells in people living with HIV.

People living with HIV treated during acute infection are the group for whom achieving functional cure appears most viable. Follicular CD8 T cells could contribute to HIV reservoir clearance by accessing via CXCR5 expression B cell follicles within lymphoid tissues, a central compartment of the HIV reservoir. This study examines peripheral follicular CD8 T cells using flow cytometry, transcriptome analyses, and functional assays in people treated during acute (n=37) and chronic (n=18) infection, as well as in individuals naturally controlling HIV (n=20) and living without HIV (n=10). Our results reveal that early, as opposed to late, treatment initiation preserves antiviral effector functions of follicular CD8 T cells, which are further enhanced by PD1 inhibition. We also identify a correlation between follicular CD8 T cells and intact proviral HIV DNA levels in acute, but not chronic, infection. Longitudinal transcriptomic analysis of peripheral effector cells post-48 weeks of suppressive therapy indicates traits of recent antigen exposure, suggesting potential recirculation into lymphoid tissue. These findings underscore the pivotal role of follicular CD8 T cells in anti-HIV responses and support investigating targeted cure strategies, such as anti-PD1 therapy, especially in individuals initiating treatment during acute infection.