Pediatric HIV reservoir in early ART: distinct immunobiology and its implications for HIV cure

Although antiretroviral therapy (ART) effectively suppresses HIV replication, the virus persists in latent reservoirs, which remain the principal barrier to achieving a cure. In infants who initiate ART within the first months of life, viral suppression coincides with a critical period of immune system development. Nevertheless, complete and sustained elimination of the virus is still elusive. Pediatric HIV reservoirs display distinct immunological features, including increased thymic output, a higher proportion of naive and central memory CD4⁺ T cells, and reduced immune exhaustion compared to adults. Early initiation of ART restricts initial reservoir seeding and is followed by continued decay during sustained suppression. The evidence for restricted seeding is quantitatively stronger, whereas decay data in children remain longitudinal and observational rather than randomised. As a result, children who receive early ART develop smaller reservoirs, present reduced viral diversity, and retain better-preserved immune function. These features, specifically a smaller and less diverse reservoir, a higher proportion of less differentiated infected cells and lower expression of exhaustion markers, may constrain clonal expansion and immune-driven viral evolution. This literature review consolidates current evidence regarding the establishment, maintenance, and dynamics of the HIV reservoir among pediatric populations. It highlights cellular and tissue compartmentalization, key immunological determinants, and the impact of assay selection on interpretations of reservoir persistence. The review further examines the consequences of these unique features for the development of cure-oriented strategies. Improving understanding of pediatric reservoir biology is essential for designing age-appropriate latency-reversing, immunotherapeutic, and gene-based interventions intended to achieve sustained ART-free remission or long-term post-treatment control.