Pro-inflammatory and anti-inflammatory immune biomarkers as predictors of neurodevelopment in young children exposed to HIV

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OBJECTIVE: Higher inflammation and lower neurodevelopmental outcomes have been reported in children exposed to HIV but uninfected (CHEU) compared to children unexposed to HIV (CHU) during infancy, but whether these differences persist in early childhood is unclear. We assessed pro-inflammatory and anti-inflammatory biomarkers and their associations with neurodevelopmental outcomes in CHEU and CHU aged 18-36 months. DESIGN: Cross-sectional study of 45 CHEU and 36 CHU aged 18-36 months enrolled in Eldoret, Kenya. METHODS: Plasma levels of 65 cytokines, chemokines, growth factors, and soluble receptors, and 16 soluble immune checkpoints (ICPs) were quantified using multiplex immunoassays. Monocyte activation (sCD14, sCD163) and endothelial activation (CD146, ICAM-1, VCAM-1) plasma levels were measured by ELISAs. Neurodevelopmental outcomes were assessed using the culturally adapted developmental assessment of cognition, language, and motor function. Predictors of neurodevelopmental outcomes were assessed using Bayesian Model Averaging of the linear regression model. RESULTS: CHEU exhibited lower levels of several chemokine and growth factors and four inflammatory cytokines compared to CHU: A proliferation inducing ligand (APRIL) ( P = 0.03), IL-12p70 ( P < 0.001), macrophage migration inhibitory factor (MIF) ( P = 0.002), and Tweak ( P = 0.003). Conversely, two soluble ICPs, CD40 ( P = 0.02) and TIM3 ( P = 0.001), were higher in CHEU compared to CHU. IL-22 and SDF-1α emerged as the strongest predictors of neurodevelopment in CHEU and CHU, respectively. CONCLUSION: In early childhood, CHEU exhibited an immunosuppressive rather than inflammatory biomarker profile. Immune biomarkers more frequently predicted neurodevelopmental outcomes than social and demographic factors, and the predictors of cognitive, motor, and language outcomes differed between CHU and CHEU. Further research is necessary to explore the connection between childhood neurodevelopment and immune biomarkers.

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