# Maternal and child immune profiles are associated with neurometabolite measures of early-life neuroinflammation in children who are HIV-exposed and uninfected: a South African birth cohort

## TL;DR

This study finds that immune markers in mothers and children are linked to brain chemistry in HIV-exposed but uninfected children, suggesting prenatal immune changes may affect early brain development.

## Contribution

The study identifies specific immune-neurometabolite associations in HIV-exposed children, highlighting potential mechanisms for neurodevelopmental risks.

## Key findings

- Higher maternal IL-5 and IL-8 were linked to increased myo-inositol in HEU children's brain regions.
- Child MMP-9 levels at two years correlated with myo-inositol in midline parietal grey matter.
- Maternal IL-13 was associated with higher glutamate in non-HEU children, with interactions modified by HIV status.

## Abstract

Children who are HIV-exposed and uninfected (HEU) are at risk of neurodevelopmental delays, potentially via prenatal immune dysregulation. We investigated whether maternal and child peripheral blood immune markers relate to early brain metabolite profiles in children with and without HIV exposure from a South African birth cohort.

Within the Drakenstein Child Health Study, a neuroimaging subgroup of children underwent single-voxel magnetic resonance spectroscopy at 23 years (n=156; 66 HEU, 90 HIV-unexposed). A panel of eighteen immune markers was quantified in blood serum of pregnant women and in their children at 7 weeks and 2 years follow-up. Neurometabolite ratios to creatine were quantified in midline parietal grey matter and left and right parietal white matter. Cross-sectional associations between immune markers and neurometabolite ratios were tested using linear models with robust standard errors, adjusting for age at scan, sex, and voxel tissue composition, and controlling for false discovery rate.

In children who were HEU, higher concentrations of maternal pro-inflammatory cytokines IL-5 (β=0.79, p=0.005) and IL-8 (β=0.64, p=0.02) were positively associated with myo-inositol ratios in midline parietal grey and right parietal white matter regions, respectively. At two years, higher child serum MMP-9 was positively associated with myo-inositol ratios in midline parietal grey matter (β=1.30, p=0.03). In children without HIV exposure, higher maternal anti-inflammatory IL-13 was associated with higher glutamate ratios in midline parietal grey matter (β=0.42, p<0.0001), and this association was significantly modified by maternal HIV (interaction β=−0.41, p=0.038).

In this South African cohort, HIV exposurespecific associations were observed between mother and child immune markers and child neurometabolite ratios at 23 years. Larger, longitudinal neuroimaging studies integrating neurodevelopmental outcomes are needed to clarify mechanisms and clinical implications.

Wider access to HIV treatment and prevention programmes in pregnancy has reduced new HIV infections in children. Because of this progress, most children born to mothers living with HIV do not acquire the virus themselves. There are over 16 million children with perinatal HIV exposure without infection worldwide, with the largest numbers in South Africa. These children face increased risks of developmental delay compared to children without HIV exposure. One possible explanation is that changes in a mother’s immune system from HIV during pregnancy may influence how her child’s brain develops.

We studied mothers and their children in a South African birth cohort. We measured immune markers (i.e., molecules the body uses as part of its immune system) in mothers during pregnancy and in their children at six weeks and at two years of age. When the children were two to three years old, they had a brain scan called magnetic resonance spectroscopy. This measured brain chemicals, including myo-inositol, which can reflect inflammation in the brain, and glutamate, which helps brain cells communicate and supports learning and memory.

We found that among children with perinatal HIV exposure, higher levels of certain immune markers in the mother’s blood were associated with higher levels of myo-inositol in the child’s brain at two to three years of age. These associations looked different in children whose mothers did not have HIV. These findings suggest that the immune environment in pregnancies affected by HIV infection may shape early brain chemistry in children.