title: Hepatitis C virus triggers apoptosis of a newly developed hepatoma cell line through antiviral defense system.
abstract: OBJECTIVE
  Hepatitis C virus (HCV) has a tendency to cause chronic viral infection. Viral evasion of host immune systems plays a key role in the pathogenesis of HCV. However, the interaction between HCV and hepatocyte innate antiviral defense systems is not understood. The aim of this study was to examine how human hepatocytes respond to HCV infection.
  
  
  METHODS
  We have established a novel human hepatoma cell line, LH86, from a well-differentiated hepatocellular carcinoma tissue. An infectious HCV isolate, JFH-1, was used to infect LH86 cells. HCV replication and apoptosis after viral infection were examined. Mechanisms of HCV-induced apoptosis were determined. Type I interferon induction and the relevant signaling molecules were examined.
  
  
  RESULTS
  LH86 cells permitted JFH-1 HCV infection. The viral infection caused massive apoptosis. The apoptosis was related to viral replication, because blocking viral entry with anti-CD81 or suppressing viral replication with interferon protected cells from HCV-induced apoptosis. The HCV-induced apoptosis appeared to be triggered by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors, death receptor 4 and death receptor 5, which were up-regulated in HCV infection. HCV also activated interferon response factor 3, which induced expression of interferon and TRAIL in LH86 cells.
  
  
  CONCLUSIONS
  Our study showed that a specific HCV isolate, JFH-1, is cytopathic in this new hepatoma cell line. LH86 cells mount an intact innate antiviral defense through induction of interferon and triggering apoptosis of infected cells. This study reveals a novel mechanism by which host hepatocytes respond to acute HCV infection.
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.
authors.forename: Haizhen
authors.initials: H
authors.lastname: Zhu
authors.forename: Huijia
authors.initials: H
authors.lastname: Dong
authors.forename: Erika
authors.initials: E
authors.lastname: Eksioglu
authors.forename: Alan
authors.initials: A
authors.lastname: Hemming
authors.forename: Mengde
authors.initials: M
authors.lastname: Cao
authors.forename: James M
authors.initials: JM
authors.lastname: Crawford
authors.forename: David R
authors.initials: DR
authors.lastname: Nelson
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000472:pathogenicity / Q000502:physiology*; D006526:Hepatitis C / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D007372:Interferons / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014779:Virus Replication / Q000502:physiology
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D007372:Interferons