Cross-disciplinary approach to understanding the long-term impact of HIV exposure in children

Neurodevelopment and school readiness are critical determinants of long-term health, educational achievement, and socioeconomic outcomes. In Sub-Saharan Africa (SSA), millions of children face suboptimal neurodevelopmental trajectories, with significant implications for their future well-being and the prosperity of their communities. One factor that clearly impairs development is exposure to infections, both in utero and after birth. While we and others have demonstrated impaired neurocognitive development in young children born HIV- exposed and uninfected (CHEU), the long-term impact of maternal HIV on child outcomes has rarely been assessed. However, CHEU may differ from those born to mothers without HIV infection (CHU) in a variety of ways that span biological, social and environmental factors. One key factor known to influence neurological development is the composition of the gut microbiota, which is thought to be altered by in utero HIV exposure. We have already enrolled and followed a cohort of infants born to mothers with and without HIV infection in Malawi and evaluated their socio-economic and nurturing environment, their post-natal health, and neurodevelopment. Here, we propose to extend the follow-up of our cohort as they reach school age. In an effort to strengthen key areas of research excellence at the Kamuzu University of Health Sciences in Blantyre Malawi, we propose establishing a core of investigators and leaders who can evaluate neurocognitive function and school readiness, lead studies of the impact of the microbiome on health, and conduct modeling to understand multifactorial health outcomes that are essential to evaluating the real-world context. While early childhood development is a key predictor of long-term health, studying older children's neurodevelopment is essential within a “life-course” perspective, which recognizes that growth, health, and development continue beyond early childhood. By considering the interconnectedness of in utero exposure, the psychosocial environment, the microbiome, and cognitive development, we can better target interventions that promote holistic development across multiple areas. The interconnectedness of these three factors makes it challenging to assess their combined and independent effects on development, particularly among older children. We will characterize these relationships in our ongoing cohort of CHEU and CHU and apply causal inference techniques to estimate the relative contributions and interactions between each of these factors. The goal of this proposal is to elucidate the role of in utero HIV exposure on the child's microbiome development and subsequent neurodevelopmental progress. We aim to identify microbiome profiles associated with both exposure to HIV in utero and neurodevelopmental outcomes. This research will be complemented by a comprehensive training component, fostering capacity building and knowledge transfer to local researchers and healthcare providers, thereby maximizing the health and well-being of this vulnerable population of children.