Abstract
BACKGROUND: Epigenetics offers insight into the mechanisms by which early life HIV infection and HIV exposure in utero affects offspring health. However, due to the widespread use of antiretroviral therapy (ART) during pregnancy/infancy, contemporary studies are unable to disentangle effects of HIV from ART exposure on epigenetic profiles. METHODS: Using historical specimens collected before widespread use of ART (1985-1991), we compared DNA methylation (DNAm) profiles among infants with perinatally-acquired HIV (PHIV), HIV-exposed but uninfected (HEU), and HIV-unexposed uninfected (HUU). DNAm in peripheral blood mononuclear cells collected at 3 and 12 months of age (36 PHIV, 33 HEU, and 33 HUU) was profiled using the Illumina Infinium MethylationEPIC BeadChip. We tested for differentially methylated (DM) CpG sites between groups at 3 and 12 months, adjusting for sex, race/ethnicity, and cell type proportions. Biological pathway enrichment analyses were conducted. FINDINGS: Comparing PHIV to HEU, there were 2 DM sites at 3 months and 11 at 12 months. Comparing PHIV to HUU, there was 1 DM CpG site at 3 months and 6 at 12 months. Immune-related pathways, including interferon-mediated signalling pathways were enriched. HIV exposure was not associated with any variation in DNA methylation, as no differences were detected between HEU vs. HUU at 3 or 12 months. INTERPRETATION: HIV infection (in the absence of ART during pregnancy/infancy) was associated with DNA methylation changes at 3 and 12 months of life in infants. Differential methylation in PHIV is related to immune processes and HIV exposure in the absence of infection does not contribute to differential methylation. FUNDING: This study was supported by funding from the National Institutes of Health (R21HD104558 to SS, K01DA053157 to SS, P30ES019776 to CJM, and P30ES005022 to ESB.