Journal of Hepatology
Volume 49, Issue 6 , Pages 899-907, December 2008

The non-structural 5A protein of hepatitis C virus exhibits genotypic differences in interferon antagonism☆

  • Ya-Hui Tsai

      Affiliations

    • Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei 100, Taiwan
    • ,
  • Wan-Fen Kuang

      Affiliations

    • Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 100, Taiwan
    • ,
  • Tsai-Yi Lu

      Affiliations

    • Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei 100, Taiwan
    • ,
  • Jia-Horng Kao

      Affiliations

    • Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 100, Taiwan
    • ,
  • Ming-Yang Lai

      Affiliations

    • Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 100, Taiwan
    • ,
  • Chun-Jen Liu

      Affiliations

    • Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 100, Taiwan
    • ,
  • Pei-Jer Chen

      Affiliations

    • Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 100, Taiwan
    • ,
  • Lih-Hwa Hwang

      Affiliations

    • Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei 100, Taiwan
    • Hepatitis Research Center, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 100, Taiwan
    • Corresponding Author InformationCorresponding author. Tel.: +886 2 28267114; fax: +886 2 28212880.

Received 9 January 2008; received in revised form 13 May 2008; accepted 26 June 2008. published online 16 September 2008.

Associate Editor: J.G. McHutchison

Background/Aims

Patients infected with hepatitis C virus (HCV) genotype 2 or 3 usually respond better to interferon (IFN) treatment than those infected with genotype 1. In this study, we investigated whether the non-structural 5A protein (NS5A) of HCV genotypes 1 and 2 (1b-NS5A and 2a-NS5A, respectively) exerted differential counteractivities against IFN treatment.

Methods

We compared the inhibitory effects of 1b-NS5As and 2a-NS5As on IFN activity. We also investigated the replication inhibition of HCV subgenomic replicons containing 1b-NS5A or 2a-NS5A in response to IFN treatment.

Results

1b-NS5As exerted more profound inhibitory effects on IFN activity than 2a-NS5As. The replication of the 2a-NS5A-containing replicons was more sensitive to IFN treatment than that of the 1b-NS5A-containing replicons. Deletion of the interferon sensitivity-determining region/protein kinase R-binding domain (PKR-BD), the V3 domain, or the C-terminus region of NS5A significantly abrogated its anti-IFN activity. Domain swapping between 1b-NS5A and 2a-NS5A in the V3 domain and/or the C-terminus region resulted in a transfer of their anti-IFN activity.

Conclusions

1b-NS5As exert higher magnitudes of IFN antagonism than do 2a-NS5As. The V3 and the C-terminus regions are responsible for the differential anti-IFN effects. This phenomenon may partly explain the genotype-linked differences in the response of HCV to IFN treatment.

Keywords: Hepatitis C virus, NS5A, Genotype, IFN antagonism

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☆ The authors who have taken part in the research of this paper declared that they do not have a relationship with the manufacturers of the materials involved either in the past or present and they did not receive funding from the manufacturers to carry out their research.

PII: S0168-8278(08)00560-6

doi:10.1016/j.jhep.2008.06.030

Journal of Hepatology
Volume 49, Issue 6 , Pages 899-907, December 2008

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