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Interferon-inducible cholesterol-25-hydroxylase restricts hepatitis C virus replication through blockage of

Anggakusuma1, Inés Romero-Brey2, Carola Berger2

  • 1Institute of Experimental Virology, Twincore Centre for Experimental and Clinical Infection Research, Hannover, Germany.

Hepatology (Baltimore, Md.)
|May 23, 2015
PubMed

Insights

Hepatitis C virus infection increases cholesterol 25-hydroxylase (CH25H) in the liver. Its product, 25-hydroxycholesterol (25HC), inhibits viral RNA replication by disrupting the HCV replication factory.

Area of Science:

  • Hepatology
  • Virology
  • Immunology

Background:

  • Hepatitis C virus (HCV) is a major global health concern, infecting 180 million people.
  • Cholesterol 25-hydroxylase (CH25H) is an interferon-stimulated gene with known antiviral activity.
  • The regulation and precise anti-HCV mechanisms of human CH25H (hCH25H) in the liver are not fully understood.

Purpose of the Study:

  • To investigate the expression and regulation of hCH25H in the context of HCV infection.
  • To characterize the antiviral effects of hCH25H and its product, 25-hydroxycholesterol (25HC), against HCV.
  • To elucidate the molecular mechanisms by which 25HC inhibits HCV infectivity.

Main Methods:

  • Analysis of hCH25H mRNA levels in HCV-positive human liver biopsies and primary hepatocytes.
  • Induction of hCH25H expression by type I interferon in primary human hepatocytes.
  • Assessment of HCV inhibition by hCH25H and 25HC in hepatoma cells and using subgenomic replicons.
  • Electron microscopy to examine the effect of 25HC on viral replication structures.

Main Results:

  • hCH25H mRNA levels were significantly elevated in HCV-infected liver tissues and cells.
  • Type I interferon was identified as a primary inducer of transient hCH25H expression.
  • hCH25H and 25HC demonstrated genotype-independent restriction of HCV infection.
  • 25HC primarily inhibited HCV RNA replication by disrupting the membranous web, the viral replication factory.

Conclusions:

  • HCV infection induces interferon-stimulated CH25H expression in vivo.
  • The enzymatic product, 25HC, acts as a potent antiviral restricting HCV RNA replication.
  • 25HC inhibits the formation of the viral replication factory, providing a novel therapeutic target.
Abstract

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