Analyses of Mitochondrial DNA and Immune Phenotyping Suggest Accelerated T-Cell Turnover in Treated HIV

Abstract

Background: HIV infection is associated with premature aging and mitochondrial integrity is compromised during the aging process. Since mitochondrial toxicity is a consequence of antiretroviral therapies (ART), we hypothesized HIV and long-term ART would correlate with immunosenescence and mitochondrial DNA (mtDNA) pathology. Setting: Thirteen older HIV-infected individuals (age >40 years) with virologic suppression (stratified by duration of ART) were compared to ten uninfected controls well-matched for age. Methods: Peripheral blood T-cells were immunophenotyped to measure immune activation, proliferation, and immunosenescence in subsets. MtDNA copies/cell and the relative abundance of mtDNA carrying the “common deletion” (RACD) were quantified by droplet digital PCR. Results: Immune activation was higher in HIV-infected individuals than uninfected in mature CD4+ T-cell subsets (CD4+TTM p=0.025, CD4+TEM p=0.0020) regardless of ART duration. Cell populations from uninfected individuals were more likely to be more senescent populations in mature CD4+ T-cell subsets (TTM p=0.017), and CD8+ (CD8+TEMRA+ p=0.0026). No differences were observed in mtDNA or RACD levels in any CD4+ T-cell subsets, while CD8+TSCM of infected individuals trended to have more mtDNA (p=0.057) and reduced RACD (p=0.0025). Conclusion: HIV-infected individuals demonstrated increased immune activation, but reduced senescence in more mature T-cell subsets. Increased mtDNA content and lower RACD in CD8+TSCM suggest immune activation driven turnover of these cells in HIV-infected persons.