Skip to Content
Merck
  • Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection.

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

Nature communications (2020-02-01)
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
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Complete Whole Transcriptome Amplification Kit, DNA polymerase included, Complete Kit with optimized enzyme to amplify total RNA in <4 hours, no 3′ bias
Sigma-Aldrich
Carbonyl cyanide 3-chlorophenylhydrazone, ≥97% (TLC), powder
Sigma-Aldrich
Milli-Mark® Anti-acetyl-Histone H3-PE Antibody, Milli-Mark®, from rabbit
Sigma-Aldrich
Dorsomorphin, ≥98% (HPLC)
Sigma-Aldrich
Milli-Mark® Anti-dimethyl-Histone H3 (Lys9)-Alexa Fluor488 Antibody, Milli-Mark®, from rabbit