Abstract
Human Immunodeficiency Virus (HIV) remains a major health challenge despite dramatic advances in treatment and prevention. People living with HIV (PLWH) continue to experience high rates of non-AIDS comorbidities, including cardiovascular, renal, pulmonary, oncologic, and neurocognitive disorders. These conditions persist under viral suppression, underscoring the lasting biological impact of infection. Epigenetic dysregulation has emerged as a key driver of these outcomes. HIV integration, viral proteins, chronic inflammation, and ART exposure have all been reported to alter DNA methylation, histone modifications, transcription factor networks, and non-coding RNA regulation. These changes extend beyond infected cells, reprogramming uninfected immune and tissue compartments. Long-lived cell populations display features of epigenetic aging contributing to chronic inflammation and multimorbidity. Epigenetic clocks consistently reveal accelerated biological aging in PLWH, linking infection to age-related disease risk. Overall, HIV should be viewed not only as a virologic condition but also as one of persistent epigenomic remodeling. Recognizing how durable reprogramming sustains inflammation, accelerates aging, and promotes comorbidity will be critical for advancing beyond viral suppression toward interventions that mitigate long-term health risks in PLWH.