Epigenetic ageing accelerates before antiretroviral therapy and decelerates after viral suppression in people with HIV in Switzerland: a longitudinal study over 17 years. The Lancet
Accelerated epigenetic ageing can occur in untreated HIV infection and is partially reversible with effective antiretroviral therapy (ART). Previously, the authors showed in a longitudinal study over 17 years in 107 people with HIV serving as their own controls a significant telomere length shortening during untreated HIV infection and no evidence of any telomere length change during suppressive ART.
In this work, Schöpf et al. aimed to investigate epigenetic ageing dynamics in the same people with HIV with longitudinal samples available during more than 8 years of untreated HIV infection and during almost 10 years of suppressive ART.
They applied 5 established epigenetic age estimators (epigenetic clocks) in peripheral blood mononuclear cells (PBMCs) in Swiss HIV Cohort Study participants before or during suppressive ART. All participants had a longitudinal set of PBMC samples available at four timepoint. The authors assessed epigenetic age acceleration (EAA) and a novel rate of epigenetic ageing.
Between March 13, 1990, and Jan 18, 2018, the authors recruited 81 people with HIV from the Swiss HIV Cohort Study. 52 (65%) of 80 patients were men, 76 (95%) were white, and the median patient age was 43 (IQR 37·5–47) years. Per year of untreated HIV infection (median observation 8·08 years, IQR 4·83–11·09), mean EAA was 0·47 years (95% CI 0·37 to 0·57) for Horvath’s clock, 0·43 years (0·3 to 0·57) for Hannum’s clock, 0·36 years (0·27 to 0·44) for SkinBlood clock, and 0·69 years (0·51 to 0·86) for PhenoAge. Per year of suppressive ART (median observation 9·8 years, IQR 7·2–11), mean EAA was –0·35 years (95% CI –0·44 to –0·27) for Horvath’s clock, –0·39 years (–0·50 to –0·27) for Hannum’s clock, –0·26 years (–0·33 to –0·18) for SkinBlood clock, and –0·49 years (–0·64 to –0·35) for PhenoAge.
These findings indicated that people with HIV epigenetically aged by a mean of 1·47 years for Horvath’s clock, 1·43 years for Hannum’s clock, 1·36 years for SkinBlood clock, and 1·69 years for PhenoAge per year of untreated HIV infection; and 0·65 years for Horvath’s clock, 0·61 years for Hannum’s clock, 0·74 years for SkinBlood clock, and 0·51 years for PhenoAge, per year of suppressive ART. GrimAge showed some change in the mean EAA during untreated HIV infection (0·10 years, 0·02 to 0·19) and suppressive ART (–0·05 years, –0·12 to 0·02). The authors obtained very similar results using the rate of epigenetic ageing. Contribution of multiple HIV-related, antiretroviral, and immunological variables, and of a DNA methylation-associated polygenic risk score to EAA was small.
In conclusion, this study shows that EAA is significantly increased during 8 years of untreated HIV infection. By contrast, ART appears to initiate a reversal of EAA that is sustained for almost 10 years of viral suppression. The effects of untreated HIV infection and of ART on epigenetic ageing appear to be clinically relevant due to their large effect compared with the smaller effects of selected clinical, immunological, and HIV-related variables and host genetics. Thus, ART appears to have a key beneficial effect on epigenetic ageing, and thereby could powerfully contribute to healthy ageing and mitigate concerns about accelerated ageing in people with HIV.