Hepatitis C virus exploits cyclophilin A to evade PKR

Elife. 2020 Jun 16:9:e52237. doi: 10.7554/eLife.52237.


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.

Keywords: cyclophilin A; hepatitis C virus; immunology; infectious disease; inflammation; innate antiviral immunity; microbiology; protein kinase R; viral evasion; virus; virus-host interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cyclophilin A / antagonists & inhibitors*
  • Cyclophilin A / immunology
  • Hepacivirus / physiology*
  • Humans
  • Interferon Regulatory Factor-1 / immunology*
  • Viral Nonstructural Proteins / metabolism*
  • Virus Replication*
  • eIF-2 Kinase / genetics*
  • eIF-2 Kinase / immunology


  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • Viral Nonstructural Proteins
  • EIF2AK2 protein, human
  • eIF-2 Kinase
  • NS-5 protein, hepatitis C virus
  • Cyclophilin A