title: Targeted impairment of innate antiviral responses in the liver of chronic hepatitis C patients.
abstract: OBJECTIVE
  Innate sensing of viral infection activates a global defense response including type I interferon (IFN) and IFN-stimulated genes (ISGs) expression. We previously reported that HCV NS3/4A protease, an essential protein in viral polyprotein processing, can abrogate antiviral signaling pathways and effectors' response when ectopically expressed in human hepatocytes by cleaving antiviral adaptor CARDIF. However, whether HCV mediates evasion of innate immunity in patients with chronic infection remains unclear.
  
  
  METHODS
  In this study, paired liver biopsies and corresponding purified hepatocytes of chronic hepatitis C patients and controls were subjected to transcriptional analysis of selected innate immune genes and to CARDIF protein detection.
  
  
  RESULTS
  We report that an antiviral response is largely supported by infected hepatocytes as demonstrated by upregulation of the representative antiviral genes ISG15, ISG56, and OASL as well as chemokines genes CXCL9, CXCL10, and CXCL11 measured in both HCV-derived liver biopsies and hepatocytes; that the mRNA levels of these indicator ISGs correlate inversely with HCV RNA level; and more importantly that expression of the early responsive IRF3-dependent genes type I IFNβ, type III IL28A/IL29, and chemokine CCL5 are severely compromised and associated to a global decrease of CARDIF adaptor in infected hepatocytes.
  
  
  CONCLUSIONS
  Altogether the data argue for a strong viral strategy that counteracts the host's early antiviral response of hepatocytes from chronic patients without impairing ISGs induced via classical IFN pathway.
authors.affiliation: Institut de Recherche en Immunologie et en Cancérologie (IRIC), Université de Montréal, Québec, Canada H3T 1J4.
authors.forename: Loubna
authors.initials: L
authors.lastname: Jouan
authors.forename: Laurent
authors.initials: L
authors.lastname: Chatel-Chaix
authors.forename: Pierre
authors.initials: P
authors.lastname: Melançon
authors.forename: Ian-Gaël
authors.initials: IG
authors.lastname: Rodrigue-Gervais
authors.forename: Valerie-Ann
authors.initials: VA
authors.lastname: Raymond
authors.forename: Subajini
authors.initials: S
authors.lastname: Selliah
authors.forename: Marc
authors.initials: M
authors.lastname: Bilodeau
authors.forename: Nathalie
authors.initials: N
authors.lastname: Grandvaux
authors.forename: Daniel
authors.initials: D
authors.lastname: Lamarre
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D018925:Chemokines / Q000235:genetics; D005260:Female; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000235:genetics; D007372:Interferons / Q000235:genetics; D008099:Liver / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; D050835:Interferon Regulatory Factors; C505371:MAVS protein, human; D012333:RNA, Messenger; D012367:RNA, Viral; D007372:Interferons