title: Cleavage of the IPS-1/Cardif/MAVS/VISA does not inhibit T cell-mediated elimination of hepatitis C virus non-structural 3/4A-expressing hepatocytes.
abstract: BACKGROUND
  Hepatitis C virus (HCV) effectively establishes persistent infection in human livers. The non-structural (NS) 3/4A complex participates in this process by cleavage of interferon beta (IFN beta) promoter stimulator-1 (IPS-1; also termed Cardif/MAVS/VISA), which inhibits responses to double stranded (ds) RNA. However, it is not known whether this effect extends beyond innate responses.
  
  
  OBJECTIVE
  To test if HCV NS3/4A affects innate and adaptive immune responses in vivo.
  
  
  METHODS
  NS3 levels were semi-quantified in human liver biopsies, transfected cells, and in transgenic (Tg) mouse livers by western blot. The effect of NS3/4A on dsRNA-mediated signalling and on the integrity of IPS-1 was analysed using in vitro translation, transfected cells and Tg mice. Cytotoxic T cell (CTL)-mediated clearance of transient firefly luciferase (FLuc)- and/or NS3/4A-Tg hepatocytes was determined using in vivo imaging and western blot.
  
  
  RESULTS
  NS3 protein levels were in a comparable range (0.1-49 microg/g tissue) in infected human livers and Tg mouse livers. Importantly, these levels of NS3/4A reduced murine innate responses to synthetic dsRNA in vivo, supporting the possibility that this occurs also in infected humans. The likely explanation for this was the NS3/4A-mediated cleavage of mouse IPS-1, albeit less efficiently than human IPS-1. Despite this, FLuc- and/or NS3/4A-expressing murine hepatocytes were effectively eliminated by hepatic CTLs, utilising the classical molecules for virus-infected cell lysis, including CD8, IFN gamma, perforin and FasL.
  
  
  CONCLUSIONS
  Although HCV NS3/4A inhibits the innate immunity, this does not prevent CTL-mediated clearance of NS3/4A-expressing hepatocytes in vivo. Thus, other HCV proteins are most likely responsible for interfering with the adaptive immunity.
authors.affiliation: Division of Clinical Microbiology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Ahlén
authors.forename: E
authors.initials: E
authors.lastname: Derk
authors.forename: M
authors.initials: M
authors.lastname: Weiland
authors.forename: J
authors.initials: J
authors.lastname: Jiao
authors.forename: N
authors.initials: N
authors.lastname: Rahbin
authors.forename: S
authors.initials: S
authors.lastname: Aleman
authors.forename: D L
authors.initials: DL
authors.lastname: Peterson
authors.forename: K
authors.initials: K
authors.lastname: Pokrovskaja
authors.forename: D
authors.initials: D
authors.lastname: Grandér
authors.forename: L
authors.initials: L
authors.lastname: Frelin
authors.forename: M
authors.initials: M
authors.lastname: Sällberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D016174:Hepacivirus / Q000276:immunology / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000821:virology; D022781:Hepatocytes / Q000276:immunology / Q000821:virology*; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000276:immunology; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000276:immunology; D013045:Species Specificity; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured; D017361:Viral Nonstructural Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D017361:Viral Nonstructural Proteins; D016899:Interferon-beta