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 neurodevelopmental outcomes in children remains a critical area requiring comprehensive investigation. People living with HIV, including pregnant women, can experience episodes of immune dysregulation even with antiretroviral treatment. An aberrant immune regulation can also be observed in HIV-exposed and uninfected (HEU) children. Immune alterations during pregnancy and early life have the potential to impact the developing brain, leading to neurodevelopmental delays in the early years of life. As the immune system plays a crucial role in brain development, any perturbations during the critical period from conception to 5 years of age might have lasting consequences on cognitive and behavioural outcomes in children who are HEU.

The purpose of this study is to investigate whether the poor neurodevelopmental outcomes observed in children who are HIV-exposed and uninfected can be explained through the intermediary influence of altered maternal and child immune profiles, and subsequent neuroimaging features, in these children. To bridge this knowledge gap, this proposal aims to integrate available peripheral blood immune, neuroimaging, and neurodevelopmental data. Through a longitudinal lens, we aim to delineate trajectories of peripheral blood levels of inflammatory and neuroimmune markers in children who are HEU and their mothers, and identify potential associations with neurometabolic and white matter microstructural manifestations. The unique context of South Africa, where the burden of HIV is substantial, may offer insights that can inform both local and global strategies for improving child health outcomes.

Research aim

This project aims to longitudinally investigate the association between (a) maternal and child circulating biomarker 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 from the Western Cape. This will be achieved by performing a secondary analysis of readily available neuroimaging and immune data, to address the need for a comprehensive understanding of the biological basis underlying neurodevelopmental outcomes in children who are HEU.

Main objectives

Objective 1

• To evaluate if peripheral blood inflammatory and neuroimmune markers measured in pregnant women living with HIV and children who are HEU at different time points (6 weeks, 24, 36, 60, and 72 months) are associated with brain metabolite levels and neurodevelopmental outcomes in these children (a) at age 2-3 years, and/or (b) at age 6-7 years, and if these associations differ from those seen in HIV-unexposed children.

Objective 2

• To evaluate if peripheral blood inflammatory and neuroimmune markers measured in pregnant women living with HIV and children who are HEU at different time points are associated with white matter microstructural measurements and neurodevelopmental outcomes in these participants (a) at age 2-3 years, and/or (b) at age 6-7 years, and if these associations differ from those seen in HIV-unexposed children.

Objective 3

• To explore if peripheral inflammatory and neuroimmune biomarker trajectories in mothers who are living with HIV and children who are HEU are associated with longitudinal trajectories of (a) brain metabolite levels, (b) white matter microstructural measurements, and/or (c) neurodevelopmental outcomes in these children, from 6 weeks* to 6 years of age, and if these associations differ from those seen in HIV-unexposed children.

Secondary objectives

• To examine whether the relationship between HIV exposure, peripheral blood biomarker levels, neurometabolite levels, and white matter microstructure measurements in children who are HEU from 6 weeks to 6 years of age (combined) predict neurodevelopmental outcomes in this group.

• To assess a potential mediating effect of peripheral blood biomarker levels, neurometabolite levels, and/or white matter microstructure measurements, in the cause-effect relationship between HIV exposure and neurodevelopmental outcomes in children who are HEU, from 6 weeks to 6 years of age.