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Both Cyclophilin Inhibitors and Direct-Acting Antivirals Prevent PKR Activation in HCV-Infected Cells

Michael Bobardt1, Udayan Chatterji1, Precious Lim1

  • 1Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.

The Open Virology Journal
|May 7, 2014
PubMed

Insights

Cyclosporine derivatives (CypI) and direct-acting antivirals (DAAs) inhibit Hepatitis C virus (HCV) replication by preventing the activation of PKR, a key interferon response protein. This suggests HCV exploits PKR to evade the host immune system.

Area of Science:

  • Virology
  • Immunology
  • Hepatitis C Research

Background:

  • Hepatitis C virus (HCV) replication relies on interactions between viral protein NS5A and host factor CypA.
  • Disruption of NS5A-CypA complexes by CypI inhibits HCV replication.
  • NS5A also interacts with PKR, a crucial component of the interferon (IFN) response pathway.

Purpose of the Study:

  • To investigate the relationship between CypA, NS5A, and PKR in the context of HCV-induced IFN response.
  • To determine the specific effects of CypI and direct-acting antivirals (DAAs) on the innate immune response components, particularly PKR.

Main Methods:

  • Analysis of protein expression and activation in HCV-infected cells treated with CypI, DAAs, or IFN.
  • Assessment of PKR activation in response to IFN and its modulation by CypI and DAAs.
  • Evaluation of the effect of CypI and DAAs on PKR activation induced by a dsRNA mimic (poly I:C).

Main Results:

  • CypI significantly prevented the activation/phosphorylation, but not expression, of IFN-induced PKR in HCV-infected cells.
  • CypI specifically affected PKR activation without impacting other innate response components like eIF2, NF-κB, IRF3, IRF9, STAT1, and STAT2.
  • Several classes of DAAs (NS3/4A protease, NS5B polymerase, NS5A inhibitors) also prevented PKR activation, similar to CypI.
  • Neither CypI nor DAAs could prevent PKR activation induced by the dsRNA mimic poly I:C.
  • PKR activation was not significantly observed in the absence of HCV infection.

Conclusions:

  • The suppression of HCV replication by any anti-HCV inhibitor (CypI or DAAs) abrogates IFN-induced PKR activation, indicating CypI's effect on PKR is not unique.
  • HCV appears to exploit PKR activation, potentially through dsRNA intermediates, to counteract the host's IFN response.
  • These findings highlight a mechanism by which HCV evades innate immunity and suggest a common pathway affected by various anti-HCV therapeutics.
Keywords:
CypIDAAsHCVIFN responseNS5APKR.

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