Background/Objectives: Pregnant people with HIV (PWH) are more likely to experience systemic inflammation than pregnant people without HIV (PWoH), which may contribute to adverse outcomes in HIV-exposed uninfected (HEU) infants; however, the underlying mechanisms are not well studied. This study examined associations between maternal inflammatory markers during pregnancy and cord blood inflammatory markers and metabolomic signatures. Methods: Between 2011 and 2025, pregnant PWH and PWoH were enrolled at 24–28 weeks of gestational age. Maternal plasma was analyzed for inflammatory markers [interleukin (IL)-6, high-sensitivity C-reactive protein (hsCRP), soluble TNF-α receptor 1 (sTNFR1) and 2 (sTNFR2), soluble CD163 (sCD163), soluble CD14 (sCD14)]. At delivery, cord blood was collected for measurement of IL-6, TNF-α, IFN-γ, and IL-10 and for targeted metabolomics by ultra-performance liquid chromatography–mass spectrometry. Spearman correlation, linear regression, and weighted correlation network analysis (WGCNA) were used to evaluate associations, stratified by HIV exposure. Results: This study included 22 PWH and 47 PWoH and their infants. Among HEU infants, but not HUU infants, maternal IL-6 correlated with cord blood TNFα (r = 0.443, p < 0.05) and maternal sTNFR1 correlated with both cord blood TNFα (r = 0.617, p < 0.05) and IFNγ (r = −0.517, p < 0.05). WGCNA identified five metabolomic modules. In the HEU group, naternal sCD14 was positively associated with a metabolomic module characterized by lysophosphotidylecholines in the HEU group. Conclusions: We identified distinct patterns in the relationships between maternal inflammation and infant immune–metabolic profiles by HIV exposure status. These findings suggest that HIV infection, even with viral suppression, may alter the maternal–fetal inflammatory interface and influence early metabolic programming.

Editorial: Frontiers in Chemistry: rising stars 2022