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

Background: 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. Methods: Within the Drakenstein Child Health Study, a neuroimaging subgroup of children underwent single-voxel magnetic resonance spectroscopy at 2–3 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. Results: 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). Maternal IL-13 was positively associated with glutamate ratios in the midline parietal grey matter of HIV-unexposed peers (β=0.42, p<0.0001), with no association in children who are HEU. Conclusions: In this South African cohort, HIV exposure-specific associations were observed between certain mother and child immune markers and child neurometabolite ratios at 2–3 years. Larger, longitudinal neuroimaging studies integrating neurodevelopmental outcomes are needed to clarify mechanisms and clinical implications.