CD8⁺T-cell priming is quantitatively but not qualitatively impaired in people with HIV-1 on antiretroviral therapy

Background:The induction of de novo CD8⁺T-cell responses is essential for protective antiviral immunity, but this process is often impaired in people with HIV-1 (PWH). We investigated the extent to which the immune competence of naive CD8⁺T cells, a key determinant of priming efficacy, could be preserved or restored in PWH via long-term antiretroviral therapy (ART).Methods:We used flow cytometry, molecular analyses of gene transcription and telomere length, and a fully validated priming assay to characterize naive CD8⁺T cells ex vivo and evaluate the induction of antigen-specific effector/memory CD8⁺T cells in vitro, comparing age-matched healthy uninfected donors (HUDs), PWH on ART, and natural HIV-1 controllers (HICs).Results:We found that naive CD8⁺T cells were numerically reduced and exhibited a trend toward shorter telomere lengths in PWH on ART compared with HUDs and HICs. These features associated with impaired priming efficacy. However, we also found that naive CD8⁺T cells were fully equipped proliferatively and transcriptionally in PWH on ART, enabling the generation of antigen-specific effector/memory CD8⁺T cells with functional and phenotypic attributes comparable to those primed from HUDs.Conclusion:Our data suggest that naive CD8⁺T cells in PWH on ART are intrinsically capable of generating functionally and phenotypically intact effector/memory CD8⁺T cells in response to antigen, despite evidence of senescence and an overall numerical reduction that compromises priming efficacy relative to HUDs and HICs.