title: Defective hepatic response to interferon and activation of suppressor of cytokine signaling 3 in chronic hepatitis C.
abstract: OBJECTIVE
  Approximately half of hepatitis C virus (HCV)-infected patients do not respond to current interferon (IFN)-alpha combination therapy. To understand IFN-alpha resistance in vivo, we examined the dynamic responses to both type I and type II IFNs, human IFN (hIFN)-alpha, -gamma, and consensus IFN, in the chimpanzee model.
  
  
  METHODS
  Naive and HCV-infected chimpanzees were treated with 3 forms of hIFNs in vivo. Quantitative real-time polymerase chain reaction was performed to evaluate the expression of IFN-stimulated genes (ISGs) in both peripheral blood mononuclear cells and liver to compare the responses to hIFN between naive and infected chimpanzees. The hepatic expression of IFN signaling components and inhibitory regulators including suppressor of cytokine signaling 3 (SOCS3) were assessed. SOCS3 expression was also evaluated in the liver of HCV-infected patients undergoing IFN treatment.
  
  
  RESULTS
  The in vivo responses to all 3 hIFNs were much lower in the HCV-infected chimpanzees than those in the naive chimpanzees. This defect was particularly evident in the liver because induction of hepatic ISGs was barely detectable in the infected animals. Following IFN administration, the expression of SOCS3 was significantly up-regulated, possibly through induction of interleukin-6, in the liver of HCV-infected chimpanzees. HCV-infected humans also showed a differential pattern of hepatic SOCS3 expression in response to IFN that is associated with treatment response.
  
  
  CONCLUSIONS
  Our data indicate a predominantly defective hepatic response to IFN in HCV-infected chimpanzees, which is probably mediated through the activation of SOCS3 and may explain the nonresponse of many HCV patients to IFN-based 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: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Feld
authors.forename: Ronda K
authors.initials: RK
authors.lastname: Sapp
authors.forename: Santosh
authors.initials: S
authors.lastname: Nanda
authors.forename: Jiing-Huey
authors.initials: JH
authors.lastname: Lin
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Blatt
authors.forename: Michael W
authors.initials: MW
authors.lastname: Fried
authors.forename: Krishna
authors.initials: K
authors.lastname: Murthy
authors.forename: T Jake
authors.initials: TJ
authors.lastname: Liang
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016022:Case-Control Studies; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007372:Interferons / Q000494:pharmacology* / Q000627:therapeutic use; D015850:Interleukin-6 / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000821:virology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D002679:Pan troglodytes; D011092:Polyethylene Glycols / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D013997:Time Factors; D017211:Treatment Failure; D014481:United States
chemical_list: D000998:Antiviral Agents; D007370:Interferon Type I; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D015850:Interleukin-6; D012333:RNA, Messenger; D012367:RNA, Viral; D011994:Recombinant Proteins; C106644:SOCS3 protein, human; D050791:STAT Transcription Factors; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D011092:Polyethylene Glycols; C050739:interferon alfacon-1; D007371:Interferon-gamma; D007372:Interferons; D053612:Janus Kinases; C100416:peginterferon alfa-2a