Abstract Infection with human immunodeficiency virus (HIV) is a chronic viral disease process. Early in infection, gut permeability is increased due to translocation of bacterial products. This leads to systemic immune activation, which is reduced but not eliminated with effective antiretroviral therapy. The presence of concomitant chronic viral hepatitis infection with hepatitis C (HCV) may exacerbate systemic immune activation, via activation of hepatic macrophages with proinflammatory downstream effects. It has been suggested that immune senescence or premature aging of immune function accompanies these events and is itself a precursor to clinical outcomes such as accelerated cardiovascular disease and neurocognitive impairment. Immune senescence may be assessed using a variety of measures including DNA methylation, telomere shortening, and changes in T-cell subsets. Cross-sectional analyses have reported varying results depending upon the cohort studied and the method utilized. In this application, we seek to compare and contrast different methods of assessing immune senescence in the setting of HCV/HIV coinfection. Using longitudinal samples from a well established, diverse, and well clinically characterized cohort, the BIRTH Study (ACTG 5294), we propose to evaluate biomarkers of immune senescence and relate them to degree of hepatic fibrosis. We will examine the relationship of HCV cure to determine how senescence biomarkers change, and we will attempt to link immune senescence to alterations in Treg subpopulations.