DNA methylation signatures of inflammation in youth living with perinatally-acquired HIV.

BACKGROUND

Epigenetic modifications may illuminate mechanisms by which HIV and antiretroviral therapy (ART) exposure during critical developmental periods affect biological pathways and chronic comorbidity risk. We examined genome-wide DNA methylation (DNAm) in youth with perinatally-acquired HIV (YPHIV) compared to perinatally HIV-exposed uninfected youth (YPHEU) at two timepoints. In YPHIV, we assessed associations of HIV RNA viral load, CD4 count, and inflammation with DNAm alterations.

METHODS

Genome-wide DNAm was measured in peripheral blood mononuclear cells from 32 YPHIV and 7 YPHEU at two timepoints separated by at least 3 years via the PHACS Adolescent Master Protocol. Differentially methylated CpG sites were evaluated genome-wide (FDR p < 0.05 and ≥ 5% methylation difference) and across 15 pre-selected targeted genes at each timepoint. Regional and pathway enrichment analyses were conducted. Among YPHIV, genome-wide associations of HIV viral load, CD4 count, and inflammation markers with DNAm were assessed.

RESULTS

No genome-wide differentially methylated CpG sites were identified between YPHIV and YPHEU at either timepoint. For targeted genes, CpG sites on PSMB9 were differentially methylated at both timepoints. Among YPHIV, neither viral load nor CD4 count was associated with DNAm. In contrast, C-reactive protein was associated with 17 and 18 CpG sites at timepoints 1 and 2, respectively, with 7 overlapping genes, including two involved in blood pressure regulation and kidney function. Interleukin-6 was associated with 3 and 2 CpG sites at timepoints 1 and 2, respectively, with 2 overlapping genes involved in fatty acid metabolism and neuronal signaling.

CONCLUSION

Markers of inflammation were associated with DNA methylation signatures in YPHIV during childhood/adolescence. These epigenetic signatures may provide insight into the inflammatory pathways that contribute to chronic comorbidity risk in YPHIV and suggest inflammation as a potential target for early intervention.