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Concomitant cytomegalovirus DNAemia is associated with sustained TNF-α elevation in HIV/AIDS: a multivariable and longitudinal analysis of immune restoration

Year: 2026

Type: article

Abstract: BACKGROUND: Despite successful viral suppression with antiretroviral therapy (ART), incomplete immune reconstitution and chronic inflammation persist in people with HIV, contributing to an increased burden of non-AIDS-defining comorbidities. Emerging evidence points to cytomegalovirus (CMV) co-infection as a critical driver of this residual inflammation. Consequently, this study aims to elucidate the specific role of CMV in sustaining inflammatory pathways in the context of HIV. METHODS: This prospective observational study included 200 participants divided into three groups: 50 with HIV/CMV co‑infection, 100 with HIV mono‑infection, and 50 healthy controls. Baseline immunophenotyping and cytokine profiling were assessed using flow cytometry and enzyme-linked immunosorbent assays. To account for baseline HIV disease severity and demographic imbalances, cross-sectional comparisons were evaluated using multivariable linear regression adjusted for age, sex, and baseline absolute CD4⁺ T-cell counts, supplemented by CD4-stratified analyses (< 100 and > 200 cells/µL). To evaluate the longitudinal impact of CMV viral load dynamics, co‑infected participants were classified after 6 months follow‑up into "CMV responders" (≥ 68% reduction in CMV DNA load) and "CMV non‑responders" (< 68% reduction or increase). RESULTS: The overall cohort was predominantly CMV IgG positive (97.5%). At baseline, the unadjusted expansion of CD8⁺ T-cells observed in HIV/CMV co-infected patients lost statistical significance after multivariable adjustment for baseline CD4⁺ counts (adjusted p = 0.150), indicating this was primarily related to advanced HIV immunosuppression. In contrast, CMV DNAemia remained independently associated with significantly elevated systemic TNF-α levels (adjusted p = 0.043). Stratified analysis revealed that this independent TNF-α elevation was particularly pronounced in patients with relatively preserved immune function (CD4 > 200 cells/µL; adjusted p = 0.042), whereas these differences were obscured in severe immunosuppression (CD4 < 100 cells/µL). Longitudinal analysis revealed that effective reduction of CMV viral load was associated with significant HIV viral suppression in responders (p = 0.0039), whereas no significant reduction was observed in non-responders (p = 0.3894), and seemingly facilitated the resolution of systemic TNF-α levels. In contrast, significant recovery of CD4⁺ T-cell absolute counts occurred in both groups (p < 0.01) and the rate of recovery did not differ significantly between CMV responders and non-responders. CONCLUSIONS: These findings suggest that CMV DNAemia is independently associated with persistent TNF-α elevation in PLWH, particularly in those with preserved CD4 + counts. Rather than directly causing broad T-cell exhaustion, CMV appears to act as a specific driver of the TNF-α inflammatory pathway. Addressing adherence to anti-CMV interventions alongside ART may offer a potential strategy for reducing long-term inflammatory risks.

Source: BMC Infectious Diseases

DOI: 10.1186/s12879-026-13560-8