Immune Selection and Reservoir Evolution Shape HIV-1 Persistence: Integrating Leukocyte Heterogeneity, Latency Mechanisms, and Emerging Cure Strategies

Despite sustained suppression of viral replication by antiretroviral therapy (ART), HIV-1 persists in long-lived and clonally expanding infected-cell populations across anatomical compartments. This persistence reflects interactions among proviral regulation, host-cell biology, immune selection, and tissue-specific microenvironments. Proviral heterogeneity in genetic integrity, transcriptional activity, inducibility, and antigen expression further influences immune recognition and susceptibility to cure interventions. This review examines the molecular mechanisms of latency, infected-cell survival and clonal maintenance, immune-driven reservoir selection, and anatomical compartmentalization, with particular emphasis on CD4+ T-cell clonal dynamics and the potential contribution of macrophage-lineage populations, including brain microglia. It also distinguishes the detection of viral nucleic acids or intact proviruses from replication competence and demonstrated contributions to viral rebound. The central conceptual contribution of this review is a dynamic, multilayer reservoir-selection framework integrating four interdependent dimensions: proviral state, infected-cell fitness, immune-mediated selection, and tissue-specific context. Rather than treating these determinants as separate mechanisms, this framework conceptualizes HIV-1 persistence as an outcome of their reciprocal interactions, which collectively shape reservoir composition, stability, and therapeutic vulnerability during ART. Emerging single-cell, spatial, and multi-omic technologies offer opportunities to characterize this complexity, although functional validation remains essential to establish biological and clinical relevance. This integrated perspective highlights the need for complementary cure strategies targeting latency, infected-cell maintenance, immune-mediated clearance, and tissue-specific barriers. Achieving durable HIV-1 remission will require mechanistically informed interventions evaluated through functional reservoir measurements and clinically meaningful outcomes.