Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection.
Valeria BariliPaola FisicaroBarbara MontaniniGreta AcerbiAnita FilippiGiovanna ForleoChiara RomualdiManuela FerracinFrancesca GuerrieriGiuseppe PedrazziCarolina BoniMarzia RossiAndrea VecchiAmalia PennaAlessandra ZeccaCristina MoriAlessandra OrlandiniElisa NegriMarco PesciMarco MassariGabriele MissaleMassimo LevreroSimone OttonelloCarlo FerrariPublished in: Nature communications (2020)
Hepatitis C virus infection (HCV) represents a unique model to characterize, from early to late stages of infection, the T cell differentiation process leading to exhaustion of human CD8+ T cells. Here we show that in early HCV infection, exhaustion-committed virus-specific CD8+ T cells display a marked upregulation of transcription associated with impaired glycolytic and mitochondrial functions, that are linked to enhanced ataxia-telangiectasia mutated (ATM) and p53 signaling. After evolution to chronic infection, exhaustion of HCV-specific T cell responses is instead characterized by a broad gene downregulation associated with a wide metabolic and anti-viral function impairment, which can be rescued by histone methyltransferase inhibitors. These results have implications not only for treatment of HCV-positive patients not responding to last-generation antivirals, but also for other chronic pathologies associated with T cell dysfunction, including cancer.
Keyphrases
- hepatitis c virus
- human immunodeficiency virus
- dna methylation
- hepatitis c virus infection
- cell proliferation
- endothelial cells
- signaling pathway
- oxidative stress
- ejection fraction
- sars cov
- poor prognosis
- squamous cell carcinoma
- young adults
- drug delivery
- long non coding rna
- copy number
- patient reported outcomes
- drug induced
- replacement therapy
- childhood cancer