Perinatal HIV exposure is associated with long-term alterations in immune marker levels in children.

BACKGROUND

HIV-exposed uninfected (HEU) children represent a little-studied growing population. We aimed to determine whether perinatal HIV exposure imparts long-term immune alterations.

METHODS

A prospective cohort including 91 children (<13 years) from México was classified into four groups: HIV unexposed-uninfected (HUU, n = 25), HEU (n = 25), HIV exposed infected with undetectable (HEIundetVL, n = 25) or detectable VL (HEIdetVL, n = 16). Sixty-four immune biomarkers were measured in each child: 55 proteins in plasma and 9 mRNAs in paired-dried blood samples

RESULTS

Principal Component Analysis revealed that HEU exhibited similarity to HEIundetVL and higher inter-individual variability than HUU. HEU children exhibited significantly higher levels of IL-17A, TIM-3, P-Selectin and CD14 mRNA along with lower levels in Serum amyloid A (SAA), IGFBP-4, myeloperoxidase and tPA compared with HUU. Despite no differences in age at diagnosis, CD4 counts, or ART exposure time between the HIV-exposed and infected groups, active infection (HEIdetVL) was associated with significant alterations in 15 markers, indicating extensive immune dysregulation. These included higher levels of myeloid activation markers (sCD14, sCD163), chemokines (CXCL10), VEGF-A, immune-checkpoints (Galectin-9, PD-1 mRNA) and markers of vascular inflammation and coagulation (tPA, ICAM-1, myeloperoxidase, N-GAL, or SAA), as well as lower levels of four immune-checkpoints (sCD86, sCD137, CTLA-4) and MMP-2, compared with HEIundetVL. Logistic regression models identified SAA, TIM-3 and IGFBP-4 as independently associated with HIV exposure, achieving an accuracy of 82 % in classifying HEU vs. HUU children, whereas downregulated sCD86, combined with elevated Galectin-9 and VEGF-A levels, were independently associated with active HIV viremia, with a classification accuracy of 92.7 %.

CONCLUSIONS

Perinatal HIV exposure induces persistent immune alterations, even in uninfected children, including elevated cytokines, immune-checkpoints, thrombosis and vascular inflammation markers. These findings suggest that, even without acquiring HIV, exposed children exhibit immunological imprints that may contribute to increased risk of adverse health outcomes.