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A Protocol for Analyzing Hepatitis C Virus Replication
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Hepatitis C virus inhibits interferon signaling through up-regulation of protein phosphatase 2A

Francois H T Duong1, Magdalena Filipowicz, Marco Tripodi

  • 1Department of Research, University Hospital Basel, Basel, Switzerland.

Gastroenterology
|December 31, 2003
PubMed
Abstract

Insights

Hepatitis C virus (HCV) impairs interferon-alpha signaling in chronic hepatitis C patients by upregulating PP2Ac, leading to STAT1 hypomethylation and reduced gene activation. This explains a key viral immune evasion mechanism.

Area of Science:

  • Hepatology
  • Virology
  • Immunology

Background:

  • Hepatitis C virus (HCV) evades host defenses to establish chronic infection.
  • HCV proteins inhibit interferon-alpha-induced Jak-STAT signaling in cell cultures and transgenic mice.
  • The inhibition of interferon-alpha signaling in chronic hepatitis C patients and its mechanisms remain unclear.

Purpose of the Study:

  • To investigate interferon-alpha signaling in liver biopsies from chronic hepatitis C patients.
  • To elucidate the molecular mechanisms by which HCV interferes with Jak-STAT signaling.

Main Methods:

  • Analysis of interferon-alpha-induced signaling in liver biopsies from chronic hepatitis C patients and controls.
  • Investigation of molecular mechanisms in cultured cells, HCV transgenic mice, and patient liver biopsies.
  • Assessment of STAT1 phosphorylation, methylation, and association with PIAS1.
  • Quantification of Protein Phosphatase 2A (PP2Ac) expression levels.

Main Results:

  • STAT1 DNA binding was impaired in chronic hepatitis C patients.
  • STAT1 phosphorylation was intact, but arginine 31 methylation was reduced, leading to hypomethylation.
  • Hypomethylated STAT1 showed increased association with PIAS1, an inhibitor of STAT DNA binding.
  • Increased PP2Ac expression was observed in HCV transgenic mice and chronic hepatitis C patients.
  • Overexpression of PP2Ac in cells mimicked the effects on STAT1 and interferon-alpha signaling.

Conclusions:

  • HCV interferes with interferon-alpha signaling through PP2Ac upregulation and STAT1 hypomethylation.
  • This leads to increased STAT1-PIAS1 association, inhibiting STAT1 DNA binding.
  • Reduced transcriptional activation of interferon-alpha-stimulated genes is a consequence of this interference.

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