CMV IgG and EBV Cell-Associated DNA Independently Associate With Veterans Aging Cohort Study Index 2.0 Scores in People With HIV on ART

BACKGROUND: People with HIV (PWH) are at increased risk for non-AIDS comorbidities despite suppressive ART. Chronic co-infections with CMV and EBV may contribute to systemic immune activation and comorbidities, but the relative contribution of viral activity vs host immune response is unclear. METHODS: 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) were measured in peripheral blood mononuclear cells by droplet digital PCR. 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. RESULTS: 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 Index 2.0. HIV CA-DNA and sex were retained in the best-fit model with trend-level significance. CONCLUSIONS: 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.