Epigenetic Age Acceleration Is Associated With HIV Infection Independently of Inflammation

People with human immunodeficiency virus (HIV) (PWH) experience epigenetic age acceleration (EAA) and earlier onset of age-related comorbidities. Contributions to EAA from systemic inflammation versus HIV-specific effects warrant further study.

We analyzed peripheral-blood cell deoxyribonucleic acid (DNA) methylation (DNAm) in persons aged 18-30 years who were born with male sex. People with sexually acquired HIV who were on antiretroviral therapy (ART) with detectable plasma viral load, as is frequent in clinical practice in the United States, were matched on demographics, substance use, smoking, and inflammation to people without HIV who were at sexual risk of HIV. Systemic inflammation was stratified by plasma C-reactive protein (CRP; low/high). Epigenetic age estimates were regressed on chronological age to test associations with HIV status and inflammation.

PWH showed significantly greater EAA than people without HIV across multiple measures at both CRP levels (all P < .001). HIV status was strongly associated with higher EAA (eg, PC-Horvath1 β = 4.59 years; PC-Horvath2 β = 5.31; and PC-PhenoAge β = 5.54; all P < .001) and shorter DNAm-derived telomere length (β = -0.23; P < .001). Plasma CRP, interleukin-6, and lipopolysaccharide-binding protein did not explain these associations. Adjustment for methylation-derived naive and memory CD4/CD8 T-cell proportions substantially attenuated the association of EAA with HIV.

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.