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

Abstract

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 (HEI^undetVL, n = 25) or detectable VL (HEI^detVL, 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 HEI^undetVL 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 (HEI^detVL) 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 HEI^undetVL. 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.