Eradication of HCV by direct antiviral agents restores mitochondrial function and energy homeostasis in peripheral blood mononuclear cells

Hepatitis C virus (HCV) adopts several immune evasion mechanisms such as in-terfering with innate immunity or promoting T- cell exhaustion. However, the recent direct- antiviral agents (DAAs) rapidly eliminate the virus, and the reper-cussions in terms of immune system balance are unknown. Here we compared the PBMCs transcriptomic profile of patients with HCV chronic infection at base-line (T0) and 12 weeks after the end of the therapy (SVR12) with DAAs. 3862 genes were differently modulated, identifying oxidative phosphorylation as the top canonical pathway differentially activated. Therefore, we dissected PBMCs bioenergetic profile by analyzing mitochondrial respiration and glycolysis at 4 timepoints: T0, 4 weeks of therapy, end of therapy (EoT), and SVR12. Maximal and reserve respiratory capacity considerably increased at EoT, persisting until SVR12. Notably, over time a significant increase was observed in respiratory chain (RC) complexes protein levels and the enzymatic activity of complexes I, II, and IV. Mitochondrial- DNA integrity improved over time, and the expression of mitochondrial biogenesis key regulators such as TFAM, Nrf- 1, and PPARGC1A significantly increased at SVR12; hence, RC complexes synthesis and mitochon-drial respiration were supported after treatment. HCV clearance with DAAS pro-foundly changed PBMCs bioenergetic profile, suggesting the immunometabolism study as a new approach to the understanding of viral immune evasion mecha-nisms and host adaptations during infections and therapies.