Metabolic derangements early in life of HIV-exposed uninfected (HEU) infants have been reported.
Pregnant HIV+ and HIV- women were enrolled with their infants in a US cohort from 2009-15. We measured insulin, C-peptide, and adipokines [metabolic (resistin, leptin) and inflammatory (Interleukin (IL)-6, Tumor Necrosis Factor-a (TNFa)] in cord blood of HEU and HIV-unexposed uninfected (HUU) infants using multiplex ELISA. Demographic, clinical, and in utero antiretroviral therapy (ART) exposure data were collected. Metabolites and lipid subspecies were measured via mass spectrometry. Linear regression models were fit to assess the association of in utero HIV exposure with cord insulin and C-peptide. Orthogonal partial least squares discriminant analysis (OPLS-DA) was used to assess if differences in metabolites and lipid subspecies discriminate between HEU and HUU infants. Elastic net regression was used to identify factors including metabolites and lipid subspecies most associated with increased cord C-peptide, stratified by in utero HIV exposure.
Of 118 infants, 56 were HEU. No differences in maternal race/ethnicity, pre-pregnancy BMI, gestational diabetes (GDM) or infant preterm birth (PTB), birth weight/length were noted. All HEU were ART-exposed (52% PI, 21% NNRTI, 9% INSTI). After adjusting for maternal age, GDM, family diabetes history, pre-pregnancy BMI, as well as infant sex, PTB, and birth weight z score, mean cord insulin (ß=0.295, p=0.03) and C-peptide (ß=0.522, p<0.01) were significantly higher in HEU vs. HUU infants. IL-6 correlated positively with C-peptide in HEU (rho=0.30, p=0.05) but not HUU infants (rho=0.08, p=0.52) while resistin correlated inversely with C-peptide in HUU (rho= -0.40, p<0.01) but not HEU. Leptin correlated positively with C-peptide in both groups (rho=0.64, p<0.01 in HEU; rho=0.26, p=0.04 in HUU). OPLS-DA showed clear group separation by metabolites and lipid subspecies. (Fig) Elastic net regression identified pre-pregnancy BMI and complex lipids with polyunsaturated side chains to be positively associated with cord C-peptide in both groups. However, in HEU but not HUU infants, arachidonic acid and microbial derivatives of tyrosine and tryptophan were associated with C-peptide.
Compared to HUU, HEU infants manifest with insulin resistance. Differences in cord metabolite, lipid subspecies, & adipokines are significant between HEU and HUU infants, suggesting altered fetal metabolic programming due to in utero HIV exposure.