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

Author

Listed:
  • Valeria Barili

    (University of Parma
    Azienda Ospedaliero–Universitaria of Parma)

  • Paola Fisicaro

    (Azienda Ospedaliero–Universitaria of Parma)

  • Barbara Montanini

    (University of Parma
    University of Parma)

  • Greta Acerbi

    (University of Parma
    Azienda Ospedaliero–Universitaria 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
    Azienda Ospedaliero–Universitaria of Parma)

  • Andrea Vecchi

    (University of Parma
    Azienda Ospedaliero–Universitaria 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
    Azienda Ospedaliero–Universitaria of Parma)

  • Marco Massari

    (IRCCS–Azienda Ospedaliera S. Maria Nuova)

  • Gabriele Missale

    (University of Parma
    Azienda Ospedaliero–Universitaria of Parma)

  • Massimo Levrero

    (Cancer Research Center of Lyon (CRCL)-INSERM U1052
    Université Claude Bernard Lyon 1, Service d’Hepatologie et Gastroenterologie Hopital de la Croix-Rousse, Hospices Civils de Lyon
    Istituto Italiano di Tecnologia)

  • Simone Ottonello

    (University of Parma
    University of Parma)

  • Carlo Ferrari

    (University of Parma
    Azienda Ospedaliero–Universitaria of Parma)

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.

Suggested Citation

  • Valeria Barili & Paola Fisicaro & Barbara Montanini & Greta Acerbi & Anita Filippi & Giovanna Forleo & Chiara Romualdi & Manuela Ferracin & Francesca Guerrieri & Giuseppe Pedrazzi & Carolina Boni & Ma, 2020. "Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection," Nature Communications, Nature, vol. 11(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14137-7
    DOI: 10.1038/s41467-019-14137-7
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