Project 3 Summary / Abstract Exposure to maternal HIV infection affects child development through complex intersecting social and biologic pathways. Lower scores for cognition, attention, processing speed, and executive function have been reported for HIV-exposed uninfected (HEU) children compared to HIV-unexposed (HUU) peers. Increasing evidence indicates that exposure to maternal HIV-associated immune activation in utero, as well as systemic chronic inflammation from infections acquired in early life, particularly cytomegalovirus (CMV), may contribute to neurodevelopmental deficits in children. CMV elicits profound immune activation and inflammation following infection, and has been associated with poorer growth, impaired motor functioning, and increased morbidity in HEU children and children living with HIV (CLHIV). East African children acquire CMV early in life, with 40-60% of HEU and HUU infected by 3 months of age. By contrast with HUU, HEU children acquire CMV earlier and experience persistent systemic CMV viremia for many months, although the consequences of this for development are currently unclear. Given the wealth of data linking early-life infections and inflammation to neurodevelopmental delays, and the hyper-inflammatory effect of CMV at a critical age for brain development, we propose to investigate the hypothesis that early acquisition of CMV and poorly-controlled CMV viremia in HEU lead to chronic inflammation and immune activation, which leads to changes in growth and development. We will leverage an existing longitudinal birth cohort study of HEU and HUU in Kenya in which enrollment and follow-up started in the third trimester of pregnancy and continued for 2 years postpartum with intensive collection of specimens and clinical data. Follow-up will be extended for 2 years to enable a detailed and sensitive assessment of multiple neurodevelopmental domains at 4 years of age. In Aim 1, we will determine the association between infant CMV infection and neurodevelopment at 4 years of age. In Aim 2, we will assess the impact of maternal and infant immune activation and inflammation on child neurodevelopment at 4 years of age. Lastly, we will conduct mediation analyses to interrogate mechanisms of inflammation and immune activation leading to neurodevelopmental deficits in HEU and HUU children (Aim 3). These studies will provide a better understanding of how early-life infections and immunologic insults contribute to long-term child neurodevelopment and will inform strategic development of interventions to improve neurodevelopmental outcomes in HEU children.