CD8+ T Cell Immunity in HIV Cure and Prevention: Linking Stemness, Spatial Niches, and Emerging Therapeutic Strategies

The central role of CD8+ T cells in HIV clearance makes them key targets in vaccine and cure strategies. This review examines our evolving understanding of CD8+ T cell-mediated HIV control and its application to curative and preventative interventions. We discuss how CD8+ T cell stemness contributes to protection along the TCF-1 (T cell factor 1) and TOX (thymocyte selection-associated high-mobility group box) axis. We highlight emerging insights, informed by novel clinical trial frameworks, into CD8+ T cell dynamics during acute HIV infection, early therapy, and treatment interruption. Furthermore, we discuss the spatial heterogeneity of CD8+ T cell function in lymphoid tissues, which underscores the antiviral potential of CD8+ T cells during chronic infections and the structural and immunological constraints that limit the clearance of HIV within follicular niches. Looking ahead, we highlight a newly developed CMV-vectored vaccine design targeting HLA-E-restricted CD8+ T cells within the broader context of HLA-E biology, along with advances in HIV chimeric antigen receptor-T cell therapy and HIV-specific T cell receptor engineering.