CMV IgG and EBV Cell-Associated DNA Independently Associate With Veterans Aging Cohort Study (VACS) Index 2.0 Scores in People With HIV on Antiretroviral Therapy.

Abstract

People with HIV (PWH) are at increased risk for non-AIDS comorbidities despite suppressive antiretroviral therapy (ART). Chronic co-infections with Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) may contribute to systemic immune activation and comorbidities, but the relative contribution of viral activity versus host immune response is unclear. We evaluated associations between viral measures and the Veterans Aging Cohort Study (VACS) Index 2.0, a validated 5-year mortality risk score for PWH. Plasma CMV and EBV IgG were quantified by ELISA, and CMV, EBV, and HIV cell-associated DNA (CA-DNA) was measured in peripheral blood mononuclear cells by ddPCR. Total globulin levels were abstracted from clinical panels as a marker of generalized immune activation. Regression models were adjusted for sex, race, ethnicity, HIV duration, and history of AIDS. Among 485 ART-suppressed PWH (mean age 54 years; 17% women; 59% White), 96.5% were CMV-seropositive, 100% EBV-seropositive, CMV CA-DNA was detected in 45.9%, EBV in 95.4%, and HIV in 99.0%. Higher VACS scores were associated with higher CMV IgG, EBV IgG, EBV CA-DNA, HIV CA-DNA, and total globulin in adjusted models. In multivariable models, CMV IgG, EBV CA-DNA, and total globulins remained independently associated with VACS 2.0. HIV CA-DNA and sex were retained in the best-fit model with trend level significance. These findings suggest distinct mechanisms by which CMV, EBV and HIV may contribute to morbidity in PWH on ART: CMV through immune activation, and EBV and HIV through viral persistence. Longitudinal studies are needed to clarify causal pathways and guide interventions.