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 influ-
ences 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,
... mehr
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, al-
though 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