title: HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons.
abstract: OBJECTIVE
  Polymorphisms in the IL28B gene have been associated with clearance of hepatitis C virus (HCV), indicating a role for type III interferons (IFNs) in HCV infection. Little is known about the function of type III IFNs in intrinsic antiviral innate immunity.
  
  
  METHODS
  We used in vivo and in vitro models to characterize the role of the type III IFNs in HCV infection and analyzed gene expression in liver biopsy samples from HCV-infected chimpanzees and patients. Messenger RNA and protein expression were studied in HCV-infected hepatoma cell lines and primary human hepatocytes.
  
  
  RESULTS
  HCV infection of primary human hepatocytes induced production of chemokines and type III IFNs, including interleukin (IL)-28, and led to expression of IFN-stimulated genes (ISGs). Chimpanzees infected with HCV showed rapid induction of hepatic type III IFN, associated with up-regulation of ISGs and minimal induction of type I IFNs. In liver biopsy specimens from HCV-infected patients, hepatic expression of IL-28 correlated with levels of ISGs but not of type I IFNs. HCV infection produced extensive changes with gene expression in addition to ISGs in primary human hepatocytes. The induction of type III IFNs is regulated by IFN regulatory factor 3 and nuclear factor κB. Type III IFNs up-regulate ISGs with a different kinetic profile than type 1 IFNs and induce a distinct set of genes, which might account for their functional differences.
  
  
  CONCLUSIONS
  HCV infection results predominantly in induction of type III IFNs in livers of humans and chimpanzees; the level of induction correlates with hepatic levels of ISGs. These findings might account for the association among IL-28, level of ISGs, and recovery from HCV infection and provide a therapeutic strategy for patients who do not respond to IFN therapy.
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Thomas
authors.forename: Veronica D
authors.initials: VD
authors.lastname: Gonzalez
authors.forename: Qisheng
authors.initials: Q
authors.lastname: Li
authors.forename: Ankit A
authors.initials: AA
authors.lastname: Modi
authors.forename: Weiping
authors.initials: W
authors.lastname: Chen
authors.forename: Mazen
authors.initials: M
authors.lastname: Noureddin
authors.forename: Yaron
authors.initials: Y
authors.lastname: Rotman
authors.forename: T Jake
authors.initials: TJ
authors.lastname: Liang
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D001706:Biopsy; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000378:metabolism; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D022781:Hepatocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D007372:Interferons / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism; D008099:Liver / Q000276:immunology* / Q000473:pathology / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism; D002679:Pan troglodytes; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D054357:Chemokine CXCL10; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D007372:Interferons; D007378:Interleukins; D016328:NF-kappa B; D012333:RNA, Messenger; C114753:CXCL10 protein, human; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494232:IRF3 protein, human