Antiviral Activities of Different Interferon Types and Subtypes against Hepatitis E Virus Replication

Antimicrob Agents Chemother. 2016 Mar 25;60(4):2132-9. doi: 10.1128/AAC.02427-15. Print 2016 Apr.


Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and a member of the genusOrthohepevirusin the familyHepeviridae HEV infections are the common cause of acute hepatitis but can also take chronic courses. Ribavirin is the treatment of choice for most patients, and type I interferon (IFN) has been evaluated in a few infected transplant patientsin vivo In this study, the antiviral effects of different exogenously administered interferons were investigated by using state-of-the-art subgenomic replicon and full-length HEV genome cell culture models. Hepatitis C virus (HCV) subgenomic replicons based on the genotype 2a JFH1 isolate served as the reference. The experiments revealed that HEV RNA replication was inhibited by the application of all types of IFN, including IFN-α (type I), IFN-γ (type II), and IFN-λ3 (type III), but to a far lesser extent than HCV replication. Simultaneous determination of interferon-stimulated gene (ISG) expression levels for all IFN types demonstrated efficient downregulation by HEV. Furthermore, different IFN-α subtypes were also able to block viral replication in combination with ribavirin. The IFN-α subtypes 2a and 2b exerted the strongest antiviral activity against HEV. In conclusion, these data demonstrate for the first time moderate anti-HEV activities of types II and III IFNs and different IFN-α subtypes. As HEV employed a potent anti-interferon mechanism by restricting ISG expression, exogenous application of IFNs as immunotherapy should be carefully assessed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Antiviral Agents / pharmacology*
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology
  • Cell Line, Tumor
  • Chemokine CXCL10 / genetics
  • Chemokine CXCL10 / immunology
  • Gene Expression Regulation
  • Genotype
  • Hep G2 Cells
  • Hepatitis E virus / drug effects*
  • Hepatitis E virus / genetics
  • Hepatitis E virus / immunology
  • Host-Pathogen Interactions
  • Humans
  • Interferon alpha-2
  • Interferon-alpha / pharmacology*
  • Interferon-gamma / pharmacology
  • Interferons
  • Interleukins / genetics
  • Interleukins / immunology
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / immunology
  • RNA-Binding Proteins
  • Recombinant Proteins / pharmacology
  • Replicon / drug effects
  • Ribavirin / pharmacology
  • Virus Replication / drug effects*


  • Adaptor Proteins, Signal Transducing
  • Antiviral Agents
  • CXCL10 protein, human
  • Carrier Proteins
  • Chemokine CXCL10
  • IFIT1 protein, human
  • IFIT3 protein, human
  • IFNL3 protein, human
  • Interferon alpha-2
  • Interferon-alpha
  • Interleukins
  • Intracellular Signaling Peptides and Proteins
  • RNA-Binding Proteins
  • Recombinant Proteins
  • Ribavirin
  • Interferon-gamma
  • Interferons

Grants and funding

Eike Steinmann was funded by a Helmholtz Centre for Infection Research intramural young investigator award and Deutsche Forschungsgemeinschaft (DFG) grant STE 1954/1-1, as well as by Bundeministerium für Bildung und Forschung (BMBF) GINACIO grant 16GW0105. Thomas Pietschmann has received consulting fees from Biotest AG and from Janssen Global Services.