Early life neuroimmune mechanisms underlying neurodevelopmental outcomes of South African children who are HIV-exposed and uninfected: A longitudinal neuroimaging and neuroinflammatory biomarkers study

Open Science Framework

This PhD project has been registered in OSF under the identifier: DOI 10.17605/OSF.IO/SN6Y9

Purpose of the study

The intersection of HIV exposure and child development is an area of growing importance, particularly in understanding how maternal HIV status influences maternal and child immune profiles and their downstream effects on brain and cognitive development. Pregnant women living with HIV may experience episodes of immune dysregulation despite antiretroviral treatment, and immune alterations are also evident in children who are HIV-exposed and uninfected (HEU). These immune disruptions during pregnancy and early life may interfere with critical brain developmental processes, potentially leading to changes in brain structure, function, and later neurodevelopmental outcomes.

This study investigates whether maternal HIV status is associated with altered maternal immune profiles and longitudinal immune trajectories in children who are HEU compared to HIV-unexposed (HU) peers. It further explores how these immune alterations relate to neurometabolic and white matter microstructural differences observed through neuroimaging (MRS and DTI) from birth to 6–7 years of age. As a secondary aim, the study also examines whether immune and neuroimaging markers show any predictive or mediation power on neurodevelopmental outcomes in HEU children, measured using standardized neurodevelopmental tools from ages 2 to 8 years.

By leveraging data from a South African longitudinal birth cohort, this project aims to delineate group differences in peripheral inflammatory and neuroimmune serum markers and identify their potential impacts on brain development. The unique context of South Africa, a region with a high burden of HIV, provides a great opportunity to generate insights that could inform targeted interventions to improve outcomes for children who are HEU, locally and globally.

Research aim

This project aims to longitudinally investigate the associations between (a) maternal and child serum marker levels, (b) brain metabolite levels and white matter microstructure, and (c) neurodevelopmental outcomes in a well-characterized cohort of South African children who are HEU and HU. The study will leverage secondary analyses of readily available immune and neuroimaging data to provide a comprehensive understanding of how maternal HIV status influences immune, brain, and developmental trajectories in HEU and HU children.

Main objectives

Objective 1

• To evaluate whether peripheral blood inflammatory and neuroimmune markers measured in pregnant women living with and without HIV, and in their children at different time points (6 weeks, 24, 36, 60, and 72 months), are associated with brain metabolite levels (measured via MR Spectroscopy) at age 2–3 years and/or age 6–7 years, and whether these associations differ between HEU and HU children based on maternal HIV status.

Objective 2

• To examine whether peripheral blood inflammatory and neuroimmune markers measured in pregnant women living with and without HIV, and in their children at different time points, are associated with white matter microstructural measurements (measured via DTI) at age 2–3 years and/or age 6–7 years, and whether these associations differ between HEU and HU children based on maternal HIV status.

Objective 3

• To investigate whether trajectories of peripheral inflammatory and neuroimmune markers in children who are HEU and HU are associated with longitudinal trajectories of (a) brain metabolite levels, (b) white matter microstructural measurements, and (c) neurodevelopmental outcomes from 6 weeks to 6–7 years of age, and whether these associations differ based on maternal HIV status.

Secondary objectives

• To explore whether the relationship between HIV exposure, peripheral blood marker levels, brain metabolite levels, and white matter microstructure in HEU children from 6 weeks to 6–7 years of age predicts neurodevelopmental outcomes in this group, compared to HU.

• To assess whether peripheral blood marker levels, brain metabolite levels, and/or white matter microstructure from 6 weeks to 6–7 years of age mediate the relationship between HIV exposure and neurodevelopmental outcomes in HEU children.