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; Carlo Ferrari

doi:10.1038/s41467-019-14137-7

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 MassariGabriele Missale, Massimo Levrero, Simone Ottonello, Carlo Ferrari

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	604
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-14137-7
Publication status	Published - Dec 1 2020

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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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., ... Ferrari, C. (2020). Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection. Nature Communications, 11(1), [604]. https://doi.org/10.1038/s41467-019-14137-7

Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection. / Barili, Valeria; Fisicaro, Paola; Montanini, Barbara; Acerbi, Greta; Filippi, Anita; Forleo, Giovanna; Romualdi, Chiara; Ferracin, Manuela; Guerrieri, Francesca; Pedrazzi, Giuseppe; Boni, Carolina; Rossi, Marzia; Vecchi, Andrea; Penna, Amalia; Zecca, Alessandra; Mori, Cristina; Orlandini, Alessandra; Negri, Elisa; Pesci, Marco; Massari, Marco; Missale, Gabriele; Levrero, Massimo; Ottonello, Simone; Ferrari, Carlo.

In: Nature Communications, Vol. 11, No. 1, 604, 01.12.2020.

Research output: Contribution to journal › Article › peer-review

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 2020, 'Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection', Nature Communications, vol. 11, no. 1, 604. https://doi.org/10.1038/s41467-019-14137-7

Barili, Valeria ; Fisicaro, Paola ; Montanini, Barbara ; Acerbi, Greta ; Filippi, Anita ; Forleo, Giovanna ; Romualdi, Chiara ; Ferracin, Manuela ; Guerrieri, Francesca ; Pedrazzi, Giuseppe ; Boni, Carolina ; Rossi, Marzia ; Vecchi, Andrea ; Penna, Amalia ; Zecca, Alessandra ; Mori, Cristina ; Orlandini, Alessandra ; Negri, Elisa ; Pesci, Marco ; Massari, Marco ; Missale, Gabriele ; Levrero, Massimo ; Ottonello, Simone ; Ferrari, Carlo. / Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection. In: Nature Communications. 2020 ; Vol. 11, No. 1.

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title = "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.",

author = "Valeria Barili and Paola Fisicaro and Barbara Montanini and Greta Acerbi and Anita Filippi and Giovanna Forleo and Chiara Romualdi and Manuela Ferracin and Francesca Guerrieri and Giuseppe Pedrazzi and Carolina Boni and Marzia Rossi and Andrea Vecchi and Amalia Penna and Alessandra Zecca and Cristina Mori and Alessandra Orlandini and Elisa Negri and Marco Pesci and Marco Massari and Gabriele Missale and Massimo Levrero and Simone Ottonello and Carlo Ferrari",

note = "Funding Information: We thank Prof. Riccardo Bonadonna (Unit of Endocrinology, University of Parma, Italy) for helpful discussions and the Microarray Facility at the University of Ferrara-Italy (http://ltta.tecnopoloferrara.it/bioinformatica.php) for help in the initial phase of bioin-formatic analysis. Access to the CoreLab (Azienda Ospedaiero-Universitaria of Parma, Italy) and to the CRBa (University of Bologna, Italy) central facility instrumentations and technical advice by Dr. Vilma Mantovani, Dr. Francesca Bianchi, Dr. Rosalia Aloe, and Dr. Roberta Musa are also gratefully acknowledged. This work also benefited from support by the Biotechnology Interuniversity Consortium (CIB) and the bioinformatics expertize framework available within the COMP-HUB Initiative, funded by the {\textquoteleft}Departments of Excellence{\textquoteright} program of the Italian Ministry for Education, University and Research (MIUR, 2018–2022). This work was supported by the European Commission grant HepAcute (FP7-HEALTH-2010), by a grant from Regione Emilia-Romagna, Italy (Programma di Ricerca Regione-Universit{\`a} 2010–2012; PRUa1RI-2012-006 to C.F., by a FIRB grant (RBAP10TPXK to C.F.) from the Italian Ministry of Education, University and Research (MIUR to C.F.), by a grant from “Agence Nationale pour la Recherche sur le SIDA et les hepatites virales” (ANRS) to M.L. (n. ECTZ66014) and by a grant from the Agence National de la Recherche (ANR@TRACTION) to M.L. Publisher Copyright: {\textcopyright} 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

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doi = "10.1038/s41467-019-14137-7",

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T1 - Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection

AU - Barili, Valeria

AU - Fisicaro, Paola

AU - Montanini, Barbara

AU - Acerbi, Greta

AU - Filippi, Anita

AU - Forleo, Giovanna

AU - Romualdi, Chiara

AU - Ferracin, Manuela

AU - Guerrieri, Francesca

AU - Pedrazzi, Giuseppe

AU - Boni, Carolina

AU - Rossi, Marzia

AU - Vecchi, Andrea

AU - Penna, Amalia

AU - Zecca, Alessandra

AU - Mori, Cristina

AU - Orlandini, Alessandra

AU - Negri, Elisa

AU - Pesci, Marco

AU - Massari, Marco

AU - Missale, Gabriele

AU - Levrero, Massimo

AU - Ottonello, Simone

AU - Ferrari, Carlo

N1 - Funding Information: We thank Prof. Riccardo Bonadonna (Unit of Endocrinology, University of Parma, Italy) for helpful discussions and the Microarray Facility at the University of Ferrara-Italy (http://ltta.tecnopoloferrara.it/bioinformatica.php) for help in the initial phase of bioin-formatic analysis. Access to the CoreLab (Azienda Ospedaiero-Universitaria of Parma, Italy) and to the CRBa (University of Bologna, Italy) central facility instrumentations and technical advice by Dr. Vilma Mantovani, Dr. Francesca Bianchi, Dr. Rosalia Aloe, and Dr. Roberta Musa are also gratefully acknowledged. This work also benefited from support by the Biotechnology Interuniversity Consortium (CIB) and the bioinformatics expertize framework available within the COMP-HUB Initiative, funded by the ‘Departments of Excellence’ program of the Italian Ministry for Education, University and Research (MIUR, 2018–2022). This work was supported by the European Commission grant HepAcute (FP7-HEALTH-2010), by a grant from Regione Emilia-Romagna, Italy (Programma di Ricerca Regione-Università 2010–2012; PRUa1RI-2012-006 to C.F., by a FIRB grant (RBAP10TPXK to C.F.) from the Italian Ministry of Education, University and Research (MIUR to C.F.), by a grant from “Agence Nationale pour la Recherche sur le SIDA et les hepatites virales” (ANRS) to M.L. (n. ECTZ66014) and by a grant from the Agence National de la Recherche (ANR@TRACTION) to M.L. Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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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