title: Hepatitis C virus replication in mouse cells is restricted by IFN-dependent and -independent mechanisms.
abstract: OBJECTIVE
  Current treatment strategies for hepatitis C virus (HCV) infection include pegylated interferon (IFN)-alfa and ribavirin. Approximately 50% of patients control HCV infection after treatment, but the broad range of patients' outcomes and responses to treatment, among all genotypes, indicates a role for host factors. Although the IFN system is important in limiting HCV replication, the virus has evolved mechanisms to circumvent the IFN response. However, direct, IFN-independent antiviral processes also might help control HCV replication. We examined the role of IFN-independent responses against HCV replication.
  
  
  METHODS
  We analyzed replication of the subgenomic JFH1 replicon in embryonic fibroblasts and primary hepatocytes from mice with disruptions in genes encoding factors in the IFN-dependent and alternative antiviral pathways (signal transducers and activators of transcription 1 [STAT1], protein kinase R, interferon regulatory factors (IRF) IRF-1, IRF-3, IRF-5, IRF-7, mitochondrial antiviral signaling molecule [MAVS], and IFN receptor [IFNAR]). We also assessed the effects of expression of these factors by mouse primary hepatocytes on HCV replication.
  
  
  RESULTS
  In addition to IRF-3- and IFN-mediated antiviral responses, IFN-independent, but IRF-1- and IRF-5-dependent mechanisms, restrict HCV replication in mouse embryonic fibroblasts. In primary hepatocytes these IFN-independent require MAVS and IRF-1.
  
  
  CONCLUSIONS
  HCV replication is limited by interferon-mediated pathways as well pathways that are independent of type I IFNs. IRF1 and IRF5 control IFN-independent signaling events that lead to antiviral responses. We observed antiviral roles of IRF1 and IRF5 that were IFN-independent and cell-type specific. These mechanisms are important in controlling viruses that interfere with the IFN signaling because cells retain the ability to induce functional but local antiviral states through expression of interferon-stimulated genes.
authors: Research Group Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors: Ramya
authors: R
authors: Nandakumar
authors: Katja
authors: K
authors: Finsterbusch
authors: Christoph
authors: C
authors: Lipps
authors: Berit
authors: B
authors: Neumann
authors: Martina
authors: M
authors: Grashoff
authors: Sharmila
authors: S
authors: Nair
authors: Inga
authors: I
authors: Hochnadel
authors: Stefan
authors: S
authors: Lienenklaus
authors: Ilka
authors: I
authors: Wappler
authors: Eike
authors: E
authors: Steinmann
authors: Hansjörg
authors: H
authors: Hauser
authors: Thomas
authors: T
authors: Pietschmann
authors: Andrea
authors: A
authors: Kröger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D005347:Fibroblasts / Q000473:pathology / Q000821:virology*; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000188:drug therapy; D022781:Hepatocytes / Q000473:pathology / Q000821:virology*; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007372:Interferons / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014779:Virus Replication / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; D050835:Interferon Regulatory Factors; D007372:Interferons; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C512612:MAVS protein, mouse; C494080:Stat1 protein, mouse
keywords: HCV; IFN; IFN-Independent; IFNAR; IRES; IRF; ISG; Interferon Regulatory Factor; JFH; JFH1 replicon with deletion of the GDD motif of NS5B; JFH1ΔGDD; Japanese fulminant hepatitis; MAVS; MEF; Mouse Embryonic Fibroblasts; PBS; PKR; Primary Mouse Hepatocytes; STAT; WT; hepatitis C virus; interferon; interferon regulatory factors; interferon-stimulated genes; internal ribosomal entry site; miR; microRNA; mitochondrial antiviral signaling molecule; mouse embryonic fibroblast; phosphate-buffered saline; protein kinase R; signal transducers and activators of transcription; type I interferon receptor; wild type