A Plasma Proteomic Ageing Clock Reflects Advanced Ageing in People with Untreated HIV and its Reduction Under Antiretroviral Therapy

Background Accelerated ageing has been associated with an increased risk of serious disease endpoints in people with HIV (PWH). We conducted a longitudinal analysis to assess accelerated proteomic ageing during untreated HIV infection and the effect of antiretroviral therapy (ART) on it by comparing the plasma proteome before and after ART initiation. Methods 416 proteins were used to train a linear regression model predicting chronological age on 727 samples from Swiss HIV Cohort Study (SHCS) participants on long-term suppressive ART (median ART duration, 11.7 years). Accelerated ageing was defined as age predicted by the proteomic ageing clock (PAC) minus chronological age. We evaluated the effect of successful ART on accelerated proteomic ageing in an independent set of 80 PWH who had 4 longitudinal samples available, that is 2 samples during untreated HIV infection (>3 years apart, median interval between samples, 8.08 years (IQR 4.83-11.09)) and 2 samples during suppressive ART (>3 years apart, median interval between samples, 9.81 years (7.16-11.01)). Findings In the longitudinal test cohort, participants showed significantly higher proteomic age during untreated HIV infection than during suppressive ART, with a mean difference of 5.99 years (95% CI 4.25, 7.72), p = 0.0001. Thus, ART was associated with a marked reduction in proteomic accelerated ageing. Although proteomic age remained higher than chronological age at all time points, trajectory analyses showed that PAC tended to converge towards chronological age with longer ART duration. We validated these findings with our previously published epigenetic ageing study in the same cohort and extended those observations to the functional proteome, showing that proteomic data can capture acute immune signatures. Further, mediation analysis suggests that reversal of accelerated ageing under ART is not driven by CD4+ or CD8+ T cell counts, indicating that the proteome captures ageing signals beyond immune reconstitution. Interpretations In a longitudinal study spanning more than 17 years, the accelerated proteomic ageing observed during untreated HIV infection showed immediate and persistent deceleration under suppressive ART, demonstrating the importance of minimising the duration of untreated HIV infection.