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.
Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection / Barili, V.; Fisicaro, P.; Montanini, B.; Acerbi, G.; Filippi, A.; Forleo, G.; Romualdi, C.; Ferracin, M.; Guerrieri, F.; Pedrazzi, G.; Boni, C.; Rossi, M.; Vecchi, A.; Penna, A.; Zecca, A.; Mori, C.; Orlandini, A.; Negri, E.; Pesci, M.; Massari, M.; Missale, G.; Levrero, M.; Ottonello, S.; Ferrari, C.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 11:1(2020), p. 604. [10.1038/s41467-019-14137-7]
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