Drug, microbiome, and immune determinants of birth and neurodevelopmental outcomes in children with exposure to HIV infection

About This Grant

Children exposed to HIV in utero but who are not infected (HEU) have been shown to have compromised growth, neurodevelopmental delays, and increased morbidity and mortality. It is critical to define mechanisms for these differences. This P01 proposes to conduct 3 Projects to examine the influence of maternal dolutegravir (DTG) and viral load (Project 1), microbiome and breastmilk human milk oligosaccharides (HMOs) (Project 2) and maternal/infant immune activation and CMV (Project 3) on outcomes in HEU children and children who are not HIV-exposed (HUU). The three Projects will use a shared Measurement and Analysis Core (MA Core) to ensure standardized child neurodevelopmental evaluations and aligned analytic approaches. The three Projects address domains of translational and mechanistic importance. DTG use is currently expanding in PMTCT programs and there are no data on child neurodevelopmental outcomes. Gut-brain connections and the role of the microbiome in neuroimmune outcomes are topics of increased interest with limited data from birth cohorts. Studies have demonstrated early differences in gut microbiome of HEU and HUU infants. Finally, marked differences in maternal immune activation and infant CMV timing occur in HEU infants which could influence growth and neurodevelopment. The three Projects will involve 3 distinct birth cohorts that will leverage 3 ongoing R01 studies led by early-stage investigators: Projects 2 and 3 will extend ongoing R01-funded HEU/HUU birth cohorts (not originally designed to assess neurodevelopment) to incorporate neurodevelopmental assessment while Project 1 will enroll a new HEU cohort and compare this cohort to a comparator R01-funded HUU birth cohort. With or without detection of differences between HEU and HUU infants, the 3 birth cohorts will provide novel insights on the influence of biologic factors on birth and neurodevelopmental outcomes. Overall P01 Aims: 1. To build a P01 structure that involves 3 Projects and 2 Cores to synergistically evaluate the influence of distinct biologic factors on birth and neurodevelopmental outcomes in HEU/HUU birth cohorts. 2. To implement a shared Measurement and Analysis Core that provides standardized training on neurodevelopmental assessments, technical input, and aligned analytic approaches between Projects. 3. To implement a shared Administrative Core to oversee shared project coordination, administration, and dissemination, convene annual meetings and to facilitate communication between the 3 Projects. The proposed P01 will cohere a group of early and established Kenyan and US investigators focused on optimizing HEU and HUU child outcomes and advance a synergistic scientific agenda that probes biologic mechanisms influencing child outcomes. The P01 will yield mechanistic and translational insights and impact and provide opportunities for collaborative development of next-generation US and Kenyan trainees.