Interferon-free Treatment for Hepatitis C Virus Infection Induces Normalization of Extrahepatic Type I Interferon Signaling

Clin Mol Hepatol. 2018 Sep;24(3):302-310. doi: 10.3350/cmh.2017.0074. Epub 2018 Mar 12.

Abstract

Background/aims: Hepatitis C virus (HCV) replicates in the peripheral blood mononuclear cells (PBMCs), leading to the production of type I interferons (IFNs). It is well known that the gene expression profile of PBMC is similar to that of the liver. The present study explored the dynamic gene expression profile of PBMCs collected from HCV-infected patients undergoing direct-acting antiviral (DAA) therapy.

Methods: A prospective cohort comprising 27 patients under DAA therapy was formed. Expression level of IFN-β and its downstream interferon-stimulated genes (ISGs) was measured in PBMCs before and after DAA treatment. Furthermore, immunoblotting was performed to identify the signaling molecules involved in the expression of ISGs.

Results: The pretreatment expression level of interferon-induced protein 44 (IFI44) and C-X-C motif chemokine ligand 10 (CXCL10) correlated with the pretreatment expression level of IFN-β. After DAA treatment, a significant decrease in the expression levels of IFN-β, IFI44, and CXCL10 was observed in the PBMCs. Furthermore, the pretreatment expression level of IFN-β and ISGs correlated with the level of signal transducer and activator of transcription 1 (STAT1) phosphorylation, and DAA treatment abrogated STAT1 phosphorylation.

Conclusion: Pretreatment activation of IFN-β response is rapidly normalized after DAA treatment. The present study suggests that the decreased type I IFN response by the clearance of HCV might contribute to DAA-induced alleviation of extrahepatic manifestation of chronic HCV infection.

Keywords: Antiviral agents; Hepatitis C virus; Interferon.

MeSH terms

  • Adult
  • Aged
  • Antigens / genetics
  • Antigens / metabolism
  • Chemokine CXCL10 / genetics
  • Chemokine CXCL10 / metabolism
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Down-Regulation / drug effects
  • Female
  • Hepacivirus / genetics
  • Hepacivirus / isolation & purification
  • Hepatitis C / drug therapy*
  • Humans
  • Interferon-beta / genetics
  • Interferon-beta / metabolism*
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Middle Aged
  • Phosphorylation / drug effects
  • Prospective Studies
  • Protease Inhibitors / pharmacology
  • Protease Inhibitors / therapeutic use*
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / drug effects

Substances

  • Antigens
  • CXCL10 protein, human
  • Chemokine CXCL10
  • Cytoskeletal Proteins
  • IFI44 protein, human
  • Protease Inhibitors
  • STAT1 Transcription Factor
  • Interferon-beta