Epigenetic age acceleration is associated with HIV infection independently of inflammation

Abstract Background People with HIV (PWH) experience epigenetic age acceleration (EAA) and earlier onset of age-related comorbidities. Contributions to premature aging from systemic inflammation versus HIV-specific effects warrant further study. Methods We analyzed peripheral-blood cell DNA methylation in persons aged 18–30 years who were born with male sex. PWH with sexually acquired HIV who were on ART with detectable plasma viral load, as is frequent in clinical practice in the U.S., were matched on demographics, substance use, smoking, and inflammation to people living without HIV who were at sexual risk of HIV. Systemic inflammation was stratified by plasma C-reactive protein (CRP; low/high) at one time point. Epigenetic age estimates at that time point were regressed on chronological age to test associations with HIV status and inflammation. Results PWH showed significantly greater EAA than people without HIV across multiple measures at both CRP levels (all p<0.001). HIV status was strongly associated with higher EAA (e.g., PC-Horvath1 β=4.59 years; PC-Horvath2 β=5.31; PC-PhenoAge β=5.54; all p<0.001) and shorter DNAm-derived telomere length (β=−0.23; p<0.001). Plasma CRP, interleukin-6, and lipopolysaccharide-binding protein did not explain these associations. Adjustment for methylation-derived naïve and memory CD4/CD8 T-cell proportions substantially attenuated the association of EAA with HIV. Conclusions Among young adult PWH with detectable viremia despite ART, EAA was more strongly associated with HIV infection than with systemic inflammation. Shifts in blood T-lymphocyte composition caused by HIV contributed to epigenetic aging observed here among PWH in a typical clinical setting in which optimal HIV suppression was not universally consistent.