Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Canada; Division of Infection and Immunity, University College London, London, United Kingdom
Sophie Ridewood
Division of Infection and Immunity, University College London, London, United Kingdom
Bethany Schneiderman
Division of Infection and Immunity, University College London, London, United Kingdom
Justin Warne
Wolfson Institute for Biomedical Research, UCL, London, United Kingdom
Keisuke Tabata
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
Caitlin F Ng
Division of Infection and Immunity, University College London, London, United Kingdom
Ralf Bartenschlager
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany; Division Virus-Associated Carcinogenesis, German Cancer Research Center, Heidelberg, Germany; German Center for Infection Research (DZIF), Heidelberg Partner Site, Heidelberg, Germany
David L Selwood
Department of Medicine, Imperial College London, London, United Kingdom
Counteracting innate immunity is essential for successful viral replication. Host cyclophilins (Cyps) have been implicated in viral evasion of host antiviral responses, although the mechanisms are still unclear. Here, we show that hepatitis C virus (HCV) co-opts the host protein CypA to aid evasion of antiviral responses dependent on the effector protein kinase R (PKR). Pharmacological inhibition of CypA rescues PKR from antagonism by HCV NS5A, leading to activation of an interferon regulatory factor-1 (IRF1)-driven cell intrinsic antiviral program that inhibits viral replication. These findings further the understanding of the complexity of Cyp-virus interactions, provide mechanistic insight into the remarkably broad antiviral spectrum of Cyp inhibitors, and uncover novel aspects of PKR activity and regulation. Collectively, our study identifies a novel antiviral mechanism that harnesses cellular antiviral immunity to suppress viral replication.
