Torque Teno Virus (TTV) Plasma Load and Immune Reconstitution in People Living with HIV: A Systematic Review

Background: Torque teno virus (TTV) is a ubiquitous, non-pathogenic component of the human virome whose role in people living with HIV (PLWH), particularly during antiretroviral therapy (ART)-mediated immune reconstitution, remains unclear. This systematic review aimed to synthesize available evidence on TTV viral load in PLWH, focusing on its relationship with immunological markers. Methods: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. A comprehensive literature search was conducted in MEDLINE, Web of Science, and Scopus in January 2026 to identify studies assessing plasma TTV viral load before and/or during ART and reporting immunological outcomes. Eligible studies included prospective and retrospective longitudinal studies, cross-sectional studies, and mixed designs assessing plasma TTV viral load in relation to ART status and immune recovery markers. Results: Thirteen studies (n = 1700 PLWH) were included, predominantly observational and conducted in adult populations. Most studies (76.9%) reported a significant inverse association between TTV viral load and CD4 T-cell count, while all studies assessing HIV viral load found a direct correlation with TTV levels. An inverse relationship with the CD4/CD8 ratio was consistently observed where evaluated. Higher TTV loads were reported in ART-naïve individuals and in those with advanced immunosuppression, with longitudinal studies indicating a general decline during ART. Overall, methodological heterogeneity and moderate risk of bias were common. Conclusions: TTV viral load shows a consistent inverse association with CD4 cell count and may reflect global immune dysfunction in PLWH beyond conventional markers. However, its clinical utility remains investigational due to the heterogeneity in the study design, limited data on longitudinal dynamics, and lack of standardized assays and thresholds.