Single-cell CD8+ dynamics in PLWH uncover the depletion of TIGIT+ memory HIV-1-specific cells during long-term ART

The expression of inhibitory receptors (IRs) is a hallmark of CD8+ T-cell exhaustion (Tex) in people living with HIV-1 (PLWH). Understanding the dynamics of IRs expression in PLWH on long-term antiretroviral treatment (ART) is critical to overcoming CD8+ Tex and designing broadly applicable HIV-1 immunotherapies for cure. To address this, we combine high-dimensional immunophenotype and unsupervised single-cell analysis of IRs and functional markers in CD8+ T-cells among 24 PLWH over a decade of ART. We found irreversible alterations of IRs co-expression patterns in CD8+ T cells and identified negative associations between the frequency of TIGIT+ and TIGIT+TIM-3+ and immune status. Moreover, the single-cell dynamics of total, polyclonal, and HIV-1-specific CD8+ T-cells delineate a complex reshaping of memory-like and effector-like cellular clusters during long-term ART. Indeed, HIV-1 specific-CD8+ T-cells dynamics uncover the selective reduction of memory-like cellular clusters sharing TIGIT expression and low CD107a. Ex vivo single TIGIT but not combinatorial TIGIT+TIM3 antibody blockade restored CD107a expression in HIV-1-specific CD8+ T cells, particularly within the memory compartment. Collectively, these results profile single-cell dynamics of IRs expression across the CD8+ T-cell landscape and propose TIGIT as a target for precision immunotherapies in PLWH on long-term ART. ### Competing Interest Statement The authors have declared no competing interest.