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Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection

Abstract : 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.
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Valeria Barili, Paola Fisicaro, Barbara Montanini, Greta Acerbi, Anita Filippi, et al.. Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection. Nature Communications, Nature Publishing Group, 2020, 11 (1), pp.604. ⟨10.1038/s41467-019-14137-7⟩. ⟨inserm-02492717⟩

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