title: IL28B inhibits hepatitis C virus replication through the JAK-STAT pathway.
abstract: OBJECTIVE
  The combination of pegylated interferon (IFN) α and ribavirin (RBV) is the standard therapy for patients with chronic HCV infection. However, it produces a sustained virologic response (SVR) in only half of the treated individuals and is associated with significant side effects. Recently, several single-nucleotide polymorphisms (SNPs) near the IL28B locus, also known as IFNλ3, were identified to be strong predictors of SVR in patients receiving PEG-IFN and RBV. We sought to determine whether IL28B was capable of inhibiting HCV replication and to determine the pathway by which IL28B exhibits anti-HCV activity.
  
  
  METHODS
  Using the full-length HCV replicon OR6 and the infectious HCV clones JFH1 and Jc1, we assessed the anti-HCV effect of IL28B on HCV and characterized the key steps of the JAK-STAT pathway by real time PCR, luciferase assay, and Western blot. Finally, we evaluated the anti-HCV effect of IL28B in the presence of JAK-STAT pathway inhibitors such as blocking antibodies, a pharmacological inhibitor, and siRNAs.
  
  
  RESULTS
  We found that IL28B inhibits HCV replication in a dose- and time-dependent manner. Like IFNα, IL28B induces the phosphorylation of STAT1 and STAT2, ISRE-driven transcription, and expression of known ISGs. The anti-HCV effects of IL28A, IL28B, and IL29 were abrogated by an IL10R2 blocking antibody, a pharmacological inhibitor of JAK1/TYK2, and by siRNA against IL28R1, STAT1, STAT2, and IRF9.
  
  
  CONCLUSIONS
  Our data demonstrate that IL28A, IL28B, and IL29 signal through the JAK-STAT pathway to inhibit HCV. These data suggest possible applications of new approaches in HCV treatment.
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Warren 1007, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. armzhang@hotmail.com
authors.forename: Leiliang
authors.initials: L
authors.lastname: Zhang
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Jilg
authors.forename: Run-Xuan
authors.initials: RX
authors.lastname: Shao
authors.forename: Wenyu
authors.initials: W
authors.lastname: Lin
authors.forename: Dahlene N
authors.initials: DN
authors.lastname: Fusco
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Kaku
authors.initials: K
authors.lastname: Goto
authors.forename: Lee F
authors.initials: LF
authors.lastname: Peng
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Chen
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007372:Interferons; D007378:Interleukins / Q000235:genetics / Q000494:pharmacology*; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide; D034741:RNA, Small Interfering / Q000235:genetics; D017471:Receptors, Interferon / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053634:TYK2 Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D017931:DNA Primers; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D007372:Interferons; D007378:Interleukins; D053613:Janus Kinase 1; D053612:Janus Kinases; D034741:RNA, Small Interfering; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D050791:STAT Transcription Factors; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D053634:TYK2 Kinase; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494227:IRF9 protein, human; C494079:STAT1 protein, human; C494084:STAT2 protein, human; C507904:JAK1 protein, human; C070139:TYK2 protein, human