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

Valeria Barili, Paola Fisicaro, Barbara Montanini, Greta Acerbi, Anita Filippi, Giovanna Forleo, Chiara Romualdi, Manuela Ferracin, Francesca Guerrieri, Giuseppe Pedrazzi, Carolina Boni, Marzia Rossi, Andrea Vecchi, Amalia Penna, Alessandra Zecca, Cristina Mori, Alessandra Orlandini, Elisa Negri, Marco Pesci, Marco Massari, Gabriele Missale, Massimo Levrero, Simone Ottonello and Carlo Ferrari ()
Additional contact information
Valeria Barili: University of Parma
Paola Fisicaro: Azienda Ospedaliero–Universitaria of Parma
Barbara Montanini: University of Parma
Greta Acerbi: University of Parma
Anita Filippi: Azienda Ospedaliero–Universitaria of Parma
Giovanna Forleo: Azienda Ospedaliero–Universitaria of Parma
Chiara Romualdi: University of Padova
Manuela Ferracin: University of Bologna
Francesca Guerrieri: Cancer Research Center of Lyon (CRCL)-INSERM U1052
Giuseppe Pedrazzi: University of Parma
Carolina Boni: Azienda Ospedaliero–Universitaria of Parma
Marzia Rossi: University of Parma
Andrea Vecchi: University of Parma
Amalia Penna: Azienda Ospedaliero–Universitaria of Parma
Alessandra Zecca: Azienda Ospedaliero–Universitaria of Parma
Cristina Mori: Azienda Ospedaliero–Universitaria of Parma
Alessandra Orlandini: Azienda Ospedaliero–Universitaria of Parma
Elisa Negri: Azienda Ospedaliero–Universitaria of Parma
Marco Pesci: University of Parma
Marco Massari: IRCCS–Azienda Ospedaliera S. Maria Nuova
Gabriele Missale: University of Parma
Massimo Levrero: Cancer Research Center of Lyon (CRCL)-INSERM U1052
Simone Ottonello: University of Parma
Carlo Ferrari: University of Parma

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: 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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14137-7

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DOI: 10.1038/s41467-019-14137-7

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