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. Copyright (C) 2023 Wolters Kluwer Health, Inc. All rights reserved.