Mapping and characterizing persistent HIV reservoirs in early-treated individuals: Implications for cure-focused interventions

Abstract

Despite the transformative impact of antiretroviral therapy (ART), HIV persists in long-lived cellular and anatomical reservoirs that reignite viral replication when treatment is interrupted. Eliminating or durably suppressing these reservoirs remains the central challenge to achieving a cure. Individuals who initiate ART during acute or early infection provide a particularly informative model, as early intervention is generally associated with reduced reservoir size, limited viral diversification, preservation of immune function, and lower levels of inflammation. These features create a valuable biological window for interrogating the earliest events of reservoir seeding and persistence. Recent advances in reservoir mapping including high-sensitivity molecular assays, full-length proviral sequencing, single-cell multi-omics, and spatial imaging have enabled increasingly refined characterization of reservoir composition, cellular identity, clonal dynamics, and tissue distribution. Studies in early-treated cohorts have identified features such as simplified clonal architecture, higher relative inducibility of intact proviruses, and, in some individuals, an increased likelihood of post-treatment control. These insights are informing the development of cure-focused interventions ranging from latency reversal and immune-based strategies to gene-editing approaches and targeted drug delivery. Nonetheless, important challenges remain, including incomplete tissue sampling, assay sensitivity limitations, and uncertainty regarding which cellular and anatomical reservoirs most critically drive viral rebound. Integrative approaches combining multi-omics profiling, predictive biomarkers, and personalized therapeutic strategies will be essential for advancing toward durable ART-free remission.