PROJECT ABSTRACT: Despite not living with HIV, HIV-exposed but uninfected (HEU) children experience higher levels of morbidity and mortality in childhood and have worse cardiometabolic outcomes, compared to HIV-unexposed (HU) children. HEU children have suboptimal immune development in early life. This increases their risk for comorbid infections in childhood, and may exacerbate cardiometabolic risk by leading to increased systemic inflammation that adversely impacts metabolic pathways. Our group has used metabolomics to characterize metabolic dysfunction starting in early life and have identified early life infections as a driver of systemic inflammation and the development of pro-atherogenic metabolic profiles in childhood. Thus, the higher burden of infections in early life among HEU children may represent and important and unexplored pathway in the pathogenesis of cardiometabolic dysfunction. In this proposal, we leverage the Drakenstein Child Health Study, a well- characterized cohort of HEU and HU participants followed from birth, to investigate how HIV-exposure and early life infections affect inflammatory response changes to the metabolome from birth to early adolescence, and evaluate how these changes influence the development of adverse cardiometabolic outcomes in early adolescence. Aim 1 will characterize longitudinal metabolomic trajectories from infancy to early adolescence using 250 metabolites among HEU (n=244) and HU (n=735) children over different developmental stages. Aim 2 will develop a set of predictive models to identify metabolomic profiles in childhood (1 and 5 years) that predict cardiometabolic dysfunction, including higher BMI/adiposity, arterial stiffness, blood pressure, dyslipidemia, and insulin resistance, in early adolescence (10 years). Aim 3 will evaluate if relationships between early life infection burden and metabolomic profiles at 10 years of age are mediated by inflammatory pathways, overall and by HIV exposure status. The proposed study will make significant contributions to the field of HIV by providing some of the first longitudinal metabolomic data from a population-based cohort of HEU and HU participants to elucidate the molecular pathways underlying the development of cardiometabolic dysfunction starting in infancy. In addition, findings from this proposal have direct clinical relevance by identifying metabolic and inflammatory biomarkers in early life to support cardiometabolic risk stratification and inform whether future intervention efforts to address cardiometabolic health in HEU should include reducing infection burden or severity. Taken together, this work will provide novel mechanistic data and biomarker identification that will inform whether HEU should be targeted for screening and intervention efforts in childhood to reduce their risk of cardiometabolic disease.