Metabolic alterations : human immunodeficiency virus (HIV)-exposed, uninfected (HEU) children

The extensive use of antiretroviral therapy (ART) and effective prevention of vertical transmission have increased the number of HIV-exposed uninfected (HEU) infants. In South Africa, approximately 30% of newborns are HEU, totaling around 270,000 children born in 2023 and 4.3 million since the introduction of ART during pregnancy. Compared to HIV-unexposed uninfected (HUU) infants, HEU infants face higher risks of immune dysfunction, severe infections, growth delays, cognitive and metabolic abnormalities, and increased morbidity and mortality, for reasons largely unknown. From a larger study, a cohort of 60 women (29 pregnant women living with HIV [PWLWH] and 31 HIV-uninfected) and their infants were selected for analysis.First, anthropometric and demographic data of mothers and infants were analysed. PWLWH were older but anthropometrically like controls, except for a larger 28-week mid-upper-arm circumference. HEU infants consistently showed reduced growth parameters compared to HUU infants. At 28 weeks' gestation, HEU foetuses had slightly smaller head and abdominal circumferences and shorter femur lengths. Post-birth, HEU infants exhibited significantly slower growth compared to HUU infants, evident at birth, six-, 10 weeks, and six months, across multiple measurements including weight, BMI, weight-for-length z-score, and BMI-for-age z-score. By six months, growth indicators in HEU infants approached normal levels, except for mid-upper arm circumference, which remained significantly lower.Next, untargeted metabolomic profiling using ¹H-NMR spectroscopy was performed on maternal plasma at 28 weeks' gestation and infant plasma at birth, six/10 weeks, and six months. Profiling revealed perturbed ketosis in PWLWH, indicated by lower 3-hydroxybutyric acid, acetoacetic acid, and acetic acid. HEU infants had lower threonine and myo-inositol, and higher formic acid at birth, lower betaine, and tyrosine at six/10 weeks, and lower 3-hydroxyisobutyric acid and higher glycine at six months compared to HUU infants. The metabolomic analysis suggested differences in plasma metabolites involved in energy utilization, growth, and infection protection between HEU and HUU infants.
Transcriptomic profiling on a small subset of infants examined microRNA (miRNA) expression differences between HEU and HUU infants at birth and between infants with normal and stunted length. Cord blood plasma from 10 infants (4 HEU, 6 HUU), matched for gestational age, sex, and HIV exposure, was analysed using RNA sequencing. Five miRNAs showed significant differential expression: Let-7, miR-143, miR-192, and miR-378 were upregulated in shorter infants, while miR-26 was downregulated in HEU infants. The upregulation of growth-suppressive miRNAs in shorter infants correlates with their stunted phenotype. The downregulation of miR-26 in HEU infants reflects findings in HIV-positive adults, indicating that HIV exposure affects infant miRNA profiles.This novel study examined metabolomic changes in PWLWH and their HEU infants compared to HIV-unexposed controls. In utero HIV/ART exposure alters key metabolites in pregnant women and their infants, with differential miRNA expression observed in shorter infants and those exposed to HIV/ART. It highlights the complex relationships between HIV/ART exposure, maternal anthropometry, infant growth, metabolite profiles, and miRNA expression. These exploratory findings will inform future research on miRNA expression in HEU and stunted infants, potentially guiding targeted interventions and monitoring to address disparities in this population.