title: Infection of Human Liver Myofibroblasts by Hepatitis C Virus: A Direct Mechanism of Liver Fibrosis in Hepatitis C.
abstract: BACKGROUND
  Chronic hepatitis C is a major cause of liver fibrosis and cirrhosis. It is generally accepted that inflammation that occurs in response to hepatocyte infection by the hepatitis C virus (HCV) is the main mechanism that triggers myofibroblast differentiation and stimulation in chronic hepatitis C. The aim of this study was to determine if HCV might infect human liver myofibroblasts (HLMF) and directly stimulate their fibrogenic activities.
  
  
  METHODS
  We evaluated the expression of the viral entry receptors, levels of HCV-RNA and HCV-protein and the expression of fibrosis markers in HLMF by using quantitative PCR, western blot and immunofluorescence analyses. Pseudoparticles (HCVpp) and cell culture-derived HCV (HCVcc) were used to study the ability of HLMF to support viral entry, replication and fibrosis induction.
  
  
  RESULTS
  We showed that HLMF expressed all known molecules of the HCV receptor complex, i.e. CD81, LDL-R, scavenger receptor-BI, claudin-1 and occludin. These cells were also permissive to HCVpp entry. Inoculation with HCVcc caused short-term infection of these cells, as shown by their content in positive- and negative-strand HCV RNA, in core and NS3 viral proteins, and by their release of core protein levels in the culture supernatants. HCV infection stimulated myofibroblastic differentiation, proliferation and collagen production in these cells. In addition, evidence of in vivo infection was provided by the detection of positive- and negative-strand HCV RNA in preparations of HLMF obtained from HCV-infected patients.
  
  
  CONCLUSIONS
  These findings indicate that HCV infection of HLMF can occur and trigger extracellular matrix overproduction, thereby contributing to the development of HCV-related liver fibrosis.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75005, Paris, France; INSERM, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France; Human HepCell, Hôpital Saint-Antoine, F-75012 Paris, France.
authors.forename: Lynda
authors.initials: L
authors.lastname: Aoudjehane
authors.affiliation: Human HepCell, Hôpital Saint-Antoine, F-75012 Paris, France.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Bisch
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75005, Paris, France; INSERM, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France; AP-HP, Hôpital Pitié-Salpêtrière, Unité de Transplantation Hépatique, F-75013, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Scatton
authors.affiliation: CIRI-International Center for Infectiology Research, Team EVIR, Université de Lyon, Lyon, France; Inserm, U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; CNRS, UMR5308, Lyon, France; LabEx Ecofect, Université de Lyon, Lyon, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Granier
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), INSERM U1016, Paris, France.
authors.forename: Jesintha
authors.initials: J
authors.lastname: Gaston
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75005, Paris, France; INSERM, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Housset
authors.affiliation: INSERM U966, Université François Rabelais and CHRU de Tours, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Roingeard
authors.affiliation: CIRI-International Center for Infectiology Research, Team EVIR, Université de Lyon, Lyon, France; Inserm, U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; CNRS, UMR5308, Lyon, France; LabEx Ecofect, Université de Lyon, Lyon, France.
authors.forename: François-Loïc
authors.initials: FL
authors.lastname: Cosset
authors.affiliation: AP-HP, Hôpital Pitié-Salpêtrière, Unité de Transplantation Hépatique, F-75013, Paris, France.
authors.forename: Fabiano
authors.initials: F
authors.lastname: Perdigao
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75005, Paris, France; INSERM, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France; AP-HP, Hôpital Saint Antoine, Département de la chirurgie digestive, F-75012, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Balladur
authors.affiliation: National Institute of Infectious Diseases, Department of Virology II, Tokyo, Japan.
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75005, Paris, France; INSERM, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France; AP-HP, Hôpital Pitié-Salpêtrière, Unité de Transplantation Hépatique, F-75013, Paris, France.
authors.forename: Yvon
authors.initials: Y
authors.lastname: Calmus
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75005, Paris, France; INSERM, UMR_S 938, CDR Saint-Antoine, F-75012, Paris, France; AP-HP, Hôpital Pitié-Salpêtrière, Unité de Transplantation Hépatique, F-75013, Paris, France.
authors.forename: Filomena
authors.initials: F
authors.lastname: Conti
mesh_terms: D000368:Aged; D062445:Claudin-1 / Q000378:metabolism; D005260:Female; D016174:Hepacivirus / Q000378:metabolism*; D019698:Hepatitis C, Chronic / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology / Q000821:virology; D062793:Occludin / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000378:metabolism; D060225:Tetraspanin 28 / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D062445:Claudin-1; D062793:Occludin; D012367:RNA, Viral; D011973:Receptors, LDL; D051122:Scavenger Receptors, Class B; D060225:Tetraspanin 28; D017361:Viral Nonstructural Proteins; C554798:CD81 protein, human; C568108:CLDN1 protein, human; C573412:LDLR protein, human; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C568985:OCLN protein, human; C495124:SCARB1 protein, human