Epigenetic aging is a hallmark of HIV pathogenesis and phenotypic outcomes

To provide a summary of epigenetic studies of HIV with a focus on DNA methylation-based biomarkers of aging. We examine first, second, and third generation epigenetic clocks, and how these biomarkers relate to molecular and phenotypic outcomes in people with HIV (PWH). Current studies show novel associations of epigenetic aging with cellular senescence, human endogenous retroviruses and transposable elements, metabolic changes, neurological injury, and sex-based aging differences in PWH. First-generation epigenetic clocks of chronological age show an average of 5–7 years of age acceleration in PWH compared to people without HIV. Second-generation epigenetic clocks demonstrate accelerated aging-related phenotypes in PWH, including greater predicted morbidity and mortality. Third-generation epigenetic clocks provide novel insights into mechanisms of aging including DNA damage and beneficial adaptations, human endogenous retroviruses and transposable DNA elements, and distinct aging patterns in different organ systems. Epigenetic clocks offer the promise of accurate, quantitative biological markers of aging in research and clinical settings for PWH.