Bifidobacterium infantis supplementation in early life to improve neurodevelopment in infants exposed to HIV - Infants who are HIV.exposed but uninfected (iHEU) represent a growing pediatric population in the United States (U.S), with evidence demonstrating higher risk of adverse health outcomes, including poorer neurodevelopmental performance during early childhood, compared with HIV.unexposed infants. Despite effective prevention of vertical HIV transmission, iHEU in the U.S. remain vulnerable to immune dysregulation and developmental delays, underscoring an urgent need to identify modifiable biological pathways that can improve long.term outcomes. One emerging pathway of interest is the early.life gut microbiome, which plays a critical role in immune maturation and neurodevelopment. iHEU have been shown to exhibit altered gut microbiome composition during infancy, characterized by reduced abundance of Bifidobacterium, particularly Bifidobacterium infantis, alongside heightened systemic inflammation. Low early.life abundance of Bifidobacterium has been associated with increased risk of neurodevelopmental delay in medically vulnerable infants, suggesting that microbiome optimization may represent a scalable intervention relevant to U.S. child health. However, mechanistic studies linking early microbiome composition, immune activation, and neurodevelopment in iHEU are limited in the U.S. due to smaller cohort sizes and difficulties with longitudinal biological sampling. South Africa provides a unique and scientifically justified setting to address this gap, with access to large, well.characterized iHEU cohorts, standardized maternal antiretroviral exposure, and established clinical trial infrastructure that enables adequately powered randomized studies not currently feasible in the U.S. alone. This project leverages an ongoing randomized, double.blind, placebo.controlled trial of oral B. infantis supplementation administered during the first month of life to 200 breastfed iHEU (R01HD109089). The trial provides rigorously collected longitudinal clinical data, biological specimens, and infrastructure to assess gut microbiome composition, immune activation, and neurodevelopment. Specific Aim 1 compares neurodevelopmental outcomes at 9 and 24 months between infants receiving B. infantis versus placebo. Specific Aim 2 evaluates longitudinal systemic inflammation associated with early microbiome modulation. Specific Aim 3 integrates microbiome, immune, and neurodevelopmental data to identify early.life biological predictors of neurodevelopment. Findings will be actively communicated back to the U.S. research and clinical community through peer.reviewed publications, conference presentations, and collaboration with U.S. investigators in pediatric HIV and neurodevelopment. By defining mechanisms relevant to iHEU, this work will inform future U.S..based intervention trials, biomarker assessment, and strategies to improve developmental outcomes among infants exposed to HIV, antiretroviral therapy, or other early.life perturbations of the gut microbiome, ensuring that all U.S. infants thrive.
