Tu182 - Amino Acid Metabolism Contribute to SIV Reservoir Size and Virus Rebound in Infants

Abstract Text: Early-life immune environments differ from adults, shaping HIV infection and disease progression. Despite antiretroviral therapy (ART), inflammation persists, driven by soluble mediators that influence immune function, reservoir persistence, and rebound post-analytical treatment interruption (ATI). The relationship between metabolites, reservoir size, and viral rebound remains unclear. We investigated host- and microbial-derived metabolites in a pediatric SIV model. Eight infant rhesus macaques (RMs), 4 weeks-old, were orally infected with SIVmac251, with ART started 4 weeks post-infection. RMs underwent ATI after 60 weeks. Plasma samples were collected longitudinally for untargeted metabolomics (LC-MS) and plasma viral load measurements. SIV reservoir was evaluated at late ART. Modulation of metabolic pathways were validated using publicly available RNA transcriptomic dataset of SHIV-infected newborn and infant RMs. Lipid and amino acid metabolism in plasma were modulated longitudinally post-infection. These plasma metabolic profiles were also observed at transcriptional levels. Pre/early ART fatty acid and non-essential amino acid metabolism were negatively and positively associated with late ART reservoir size, respectively. Of note, amino acid metabolism during ART also contributed to reservoir maintenance and consequently to higher viral rebound post-ATI, while fatty acid metabolism showed inverse associations. This data indicates that the modulation of these pathways could modulate reservoir persistence. Amino acid metabolism can potentially promote viral persistence by supporting CD4+ T cell activation and proliferation. Further validation of the direct role of these pathways in the immune system and in the reservoir maintenance are ongoing and could support new approaches for HIV cure.