TY - JOUR
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85078710344&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078710344&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-14137-7
DO - 10.1038/s41467-019-14137-7
M3 - Article
C2 - 32001678
AN - SCOPUS:85078710344
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 604
ER -