Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA

HIV-infected individuals are living longer on antiretroviral therapy, but many patients display signs that in some ways resemble premature aging. To investigate and quantify the impact of chronic HIV infection on aging, we report a global analysis of the whole-blood DNA methylomes of 137 HIV+ individuals under sustained therapy along with 44 matched HIV− individuals. First, we develop and validate epigenetic models of aging that are independent of blood cell composition. Using these models, we find that both chronic and recent HIV infection lead to an average aging advancement of 4.9 years, increasing expected mortality risk by 19%. In addition, sustained infection results in global deregulation of the methylome across >80,000 CpGs and specific hypomethylation of the region encoding the human leukocyte antigen locus (HLA). We find that decreased HLA methylation is predictive of lower CD4 / CD8 T cell ratio, linking molecular aging, epigenetic regulation, and disease progression. [Display omitted] •Methylome-wide analysis of HIV chronically infected, cART treated individuals•HIV+ individuals have an epigenetic age 4.9 years older than healthy controls•HLA locus is hypomethylated in HIV+ individuals•HIV methylation aging signature is validated in purified cells Gross et al. investigate the impact of chronic HIV infection by profiling the DNA methylomes of HIV+ individuals and matched HIV− controls. Using epigenetic models of aging, they observe that HIV+ individuals show an age advancement of 4.9 years in whole blood and validate these results in pure cell samples.