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Hepatitis C virus NS5A protein inhibits interferon antiviral activity, but the effects do not correlate with clinical

M Paterson1, C D Laxton, H C Thomas

  • 1Imperial College of Medicine at St. Mary's Campus, London, England.

Gastroenterology
|October 27, 1999
PubMed
Abstract

Insights

Hepatitis C virus NS5A protein inhibits interferon-alfa (IFN-alpha) antiviral effects in cells. This inhibition is not solely determined by the ISDR region and does not correlate with patient treatment outcomes.

Area of Science:

  • Virology
  • Immunology
  • Hepatology

Background:

  • Chronic hepatitis C virus (HCV) infection treatment with interferon-alfa (IFN-alpha) has limited long-term efficacy.
  • The HCV genotype 1 NS5A protein's Interferon Sensitivity Determining Region (ISDR) has been linked to treatment outcomes.
  • NS5A protein interaction with PKR and inhibition of IFN-alpha signaling in human cells are known.

Purpose of the Study:

  • To investigate the inhibitory effects of NS5A protein from IFN-alpha responders and non-responders on IFN-alpha's antiviral activity in vitro.
  • To determine if NS5A from non-responders exhibits greater inhibition of IFN-alpha compared to responders.

Main Methods:

  • Cloning and expression of NS5A from well-characterized hepatitis C patients in a human fibroblast cell line using an inducible promoter.
  • Controlled NS5A expression levels to assess its impact on IFN-alpha's protective effects against encephalomyocarditis virus.

Main Results:

  • NS5A expression demonstrated dose-dependent blockage of IFN-alpha's antiviral activity in human cells.
  • NS5A clones from an IFN-alpha responder showed significantly greater inhibition than those from a non-responder.
  • ISDR sequence variations had minimal impact on the degree of IFN-alpha inhibition observed.

Conclusions:

  • NS5A-mediated inhibition of IFN-alpha's antiviral effects is not exclusively regulated by the ISDR.
  • The in vitro inhibitory activity of NS5A does not directly correlate with patient responses to IFN-alpha treatment.

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