The place to be: HIV persistence within tissue reservoirs

PURPOSE OF REVIEW: HIV persists despite effective antiretroviral therapy (ART) due to long-lived reservoirs that resist immune clearance. In people with HIV (PWH) on ART, most infected cells reside in tissues rather than in circulation. Understanding how tissue environments shape HIV persistence and immune control has therefore become central to the development of curative strategies. This review summarizes recent advances in the anatomical, cellular, and immunological mechanisms that contribute to HIV persistence in tissues during ART. RECENT FINDINGS: Studies combining human tissues, non-human primate models, and single-cell and spatial technologies have revealed that HIV reservoirs are widely distributed across lymphoid and non-lymphoid tissues. Tissue-resident CD4+ T cell populations, including Th17 and T follicular helper cells, represent major cellular reservoirs. Tissue microenvironments influence HIV transcription and may support transcriptionally active reservoirs capable of contributing to viral rebound following treatment interruption. In parallel, HIV-specific CD8+ T cells persist during ART and may sense residual antigen production, but their ability to control infection in tissues can be limited by local immunoregulatory niches and intrinsic resistance mechanisms in reservoir cells. SUMMARY: These findings highlight tissues as key sites governing HIV persistence and immune control, underscoring the need for therapeutic strategies that target tissue reservoirs to achieve durable HIV remission.