Accelerated Epigenetic Aging and Methylation Disruptions Occur in Human Immunodeficiency Virus Infection Prior to Antiretroviral Therapy.

BACKGROUND Whether accelerated aging develops over the course of chronic HIV infection or can be observed prior to significant immunosuppression on is unknown. We studied DNA methylation in blood to estimate cellular aging in persons living with HIV (PLWH) prior to the initiation of antiretroviral therapy. METHODS 378 antiretroviral therapy-naive PLWH with CD4 T cell counts >500 cells/mm 3 enrolled in the Strategic Timing of Antiretroviral Therapy trial (Pulmonary Substudy) were compared to 34 HIV-negative controls. DNA methylation was performed using the Illumina MethylationEPIC BeadChip. Differentially methylated positions (DMPs) and regions (DMRs) in PLWH compared to controls were identified using a robust linear model. Methylation age was calculated using a previously described epigenetic clock. RESULTS There were a total of 56,639 DMPs and 6,103 DMRs at a false discovery rate<0.1. The top 5 DMPs corresponded to genes NLRC5, VRK2, B2M, and GPR6 and were highly enriched for cancer-related pathways. PLWH had significantly higher methylation age compared to HIV-negative controls (p=0.001), with black race, low CD4, high CD8 T cell counts, and duration of HIV being risk factors for age acceleration. CONCLUSIONS PLWH prior to the initiation of antiretroviral therapy and with preserved immune status show evidence of advanced methylation aging.