A small percentage of people living with HIV (PLHIV) spontaneously regulate viral replication without suppressive antiretroviral treatment (ART) and are categorized into 'elite controllers' (EC, HIV-RNA < 50 c/mL) and 'viremic controllers' (VC, HIV-RNA between 50-10,000 c/ml). Some EC and VC may lose controller status in time. Here we provide extensive plasma proteomics to identify biomarkers and pathways related to spontaneous viral control and its long-term preservation among 36 EC and 147 VC (discovery) and 14 EC and 5 VC (validation). VC exhibited higher concentrations of CRTAM, LY9, and CD6 and lower concentrations of VAT1 compared to EC in both the discovery and validation cohort. Longitudinal analysis of pre- and post-ART samples (median follow-up: 5.3 years) revealed downregulation of various immune-related proteins in both EC and VC. Over a 17-year follow-up period, loss of viral control occurred in 31% of VC and 3% of EC. T-cell associated proteins (CRTAM, LY9, CD6), along with ICAM3, SH2D1A, C1QL2, and CNGB3, predicted loss of viral control years before its occurrence. Markers of chronic immune activation (sPD-L1, sCD25, IL-10, TGF-β, IFN-γ, and TNF-α) and systemic inflammation (TNF, IL-1β, IL-6, and sCD14) were not predictive. Our findings underscore the dynamic interplay between T cell function and viral replication in maintaining HIV control and identify key biomarkers that predict viral load surges.
© 2026. The Author(s).