title: CD40 inhibits replication of hepatitis C virus in primary human hepatocytes by c-Jun N terminal kinase activation independent from the interferon pathway.
abstract: CD40, a member of the tumor necrosis factor receptor family, and its ligand, CD40L (CD154), are important regulators of the antiviral immune response. CD40L is up-regulated on lymphocytes and CD40 on hepatocytes during infection with hepatitis C virus (HCV); we investigated the role of CD40 signaling during HCV replication in hepatocytes. Viral replication was studied in primary human hepatocytes (PHH) and Huh7.5 cells using the infectious HCV Japanese fulminate hepatitis 1 isolate (JFH1) culture system, and in coculture with HCV antigen-specific CD8+ T cells. CD40L rapidly and transiently inhibits expression of the HCV nonstructural proteins NS3 and NS5A as well as HCV structural proteins core and E2 in Huh7.5 cells. Similarly, CD40L prevented replication of HCV in PHH, in synergy with interferon (IFN)-alpha. In Huh7.5 cells with replicating HCV, CD40L prevented production of infectious viral particles. When HCV antigen-specific CD8+ T cells were cocultured with HLA-A2-expressing Huh7 cells that had replicating virus, the T cells became activated, up-regulated CD40L, and inhibited HCV replication. Inhibition of CD40L partially prevented the antiviral activity of the CD8+ T cells. The antiviral effect of CD40L required activation of c-Jun N terminal kinases (JNK)1/2, but not induction of apoptosis or the JAK/STAT pathway that is necessary for the antiviral effects of IFNs.
  
  
  CONCLUSIONS
  CD40 inhibits HCV replication by a novel, innate immune mechanism. This pathway might mediate viral clearance, and disruptions might be involved in the pathogenesis of HCV infection.
authors: Department of Medicine II, University of Freiburg, Germany.
authors: Sibylle J
authors: SJ
authors: Rau
authors: Eberhard
authors: E
authors: Hildt
authors: Kiyoshi
authors: K
authors: Himmelsbach
authors: Robert
authors: R
authors: Thimme
authors: Takaji
authors: T
authors: Wakita
authors: Hubert E
authors: HE
authors: Blum
authors: Richard
authors: R
authors: Fischer
mesh_terms: D017209:Apoptosis; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004789:Enzyme Activation; D016174:Hepacivirus / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D006526:Hepatitis C / Q000276:immunology* / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D050791:STAT Transcription Factors / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism; D014771:Virion / Q000502:physiology; D014779:Virus Replication
chemical_list: D019013:CD40 Antigens; D016898:Interferon-alpha; D050791:STAT Transcription Factors; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human; D023201:CD40 Ligand; D053612:Janus Kinases; D048031:JNK Mitogen-Activated Protein Kinases