title: Early inhibition of hepatocyte innate responses by hepatitis B virus.
abstract: OBJECTIVE
  The outcome of hepatitis B virus (HBV) infection may be influenced by early interactions between the virus and hepatocyte innate immune responses. To date, the study of such interactions during the very early step of infection has not been adequately investigated.
  
  
  METHODS
  We used the HepaRG cell line, as well as primary human hepatocytes to analyze, within 24h of exposure to HBV, either delivered by a physiologic route or baculovirus vector (Bac-HBV), the early modulation of the expression of selected antiviral/pro-inflammatory cytokines and interferon stimulated genes. Experiments were also performed in the presence or absence of innate receptor agonists to investigate early HBV-induced blockade of innate responses.
  
  
  RESULTS
  We show that hepatocytes themselves could detect HBV, and express innate genes when exposed to either HBV virions or Bac-HBV. Whereas Bac-HBV triggered a strong antiviral cytokine secretion followed by the clearance of replicative intermediates, a physiologic HBV exposure led to an abortive response. The early inhibition of innate response by HBV was mainly evidenced on Toll-like receptor 3 and RIG-I/MDA5 signaling pathways upon engagement with exogenous agonist, leading to a decreased expression of several pro-inflammatory and antiviral cytokine genes. Finally, we demonstrate that this early inhibition of dsRNA-mediated response is due to factor(s) present in the HBV inoculum, but not being HBsAg or HBeAg themselves, and does not require de novo viral protein synthesis and replication.
  
  
  CONCLUSIONS
  Our data provide strong evidence that HBV viral particles themselves can readily inhibit host innate immune responses upon virion/cell interactions, and may explain, at least partially, the "stealthy" character of HBV.
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon 69008, France; University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France.
authors.forename: Souphalone
authors.initials: S
authors.lastname: Luangsay
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon 69008, France; University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Gruffaz
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon 69008, France; University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Isorce
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon 69008, France; University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Testoni
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon 69008, France; University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Michelet
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon 69008, France; University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Faure-Dupuy
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon 69008, France; University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Maadadi
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon 69008, France; University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France.
authors.forename: Malika
authors.initials: M
authors.lastname: Ait-Goughoulte
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon 69008, France; University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Parent
authors.affiliation: Centre Léon Bérard (CLB), Lyon 69008, France; INSERM U1032, 69003 Lyon, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Rivoire
authors.affiliation: Hoffmann-La Roche Ltd, Roche Pharmaceutical Research and Early Development, 4070 Basel, Switzerland.
authors.forename: Hassan
authors.initials: H
authors.lastname: Javanbakht
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon 69008, France; University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Lucifora
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon 69008, France; University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France. Electronic address: david.durantel@inserm.fr.
authors.forename: David
authors.initials: D
authors.lastname: Durantel
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon 69008, France; University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France; Hospices Civils de Lyon (HCL), 69002 Lyon, France; Institut Universitaire de France (IUF), 75005 Paris, France. Electronic address: fabien.zoulim@inserm.fr.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D015870:Gene Expression; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000276:immunology; D006513:Hepatitis B e Antigens / Q000235:genetics / Q000276:immunology; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D022781:Hepatocytes / Q000276:immunology* / Q000821:virology*; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis; D012330:RNA, Double-Stranded / Q000235:genetics / Q000276:immunology
chemical_list: D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; C508600:IL6 protein, human; D015850:Interleukin-6; D012330:RNA, Double-Stranded
keywords: Early host/virus interaction; Hepatitis B virus; Hepatocytes; IFN response; dsRNA-mediated innate immunity