title: Hepatitis C virions subvert natural killer cell activation to generate a cytokine environment permissive for infection.
abstract: OBJECTIVE
  Hepatitis C virus (HCV) is remarkably successful in establishing persistent infections due to its ability to evade host immune responses through a combination of mechanisms including modulation of interferon (IFN) signalling in infected cells, interference with effector cell function of the immune system and continual viral genetic variation. We have previously demonstrated that natural killer (NK) cells can be inhibited in vitro by recombinant HCV glycoprotein E2 via cross-linking of CD81, a cellular co-receptor for the virus.
  
  
  METHODS
  Taking advantage of the recently established tissue-culture system for HCV, we have studied the effects of CD81 engagement by the HCV envelope glycoprotein E2 when the protein is part of complete, infectious viral particles. Specifically, we asked whether exposure to HCV viral particles (HCVcc) affects activation of NK cells and whether altered NK cell activation, in turn, impacts on HCV infectivity.
  
  
  RESULTS
  We found that immobilized HCVcc, unlike soluble HCVcc, inhibited IFN-gamma production by interleukin (IL)-12 activated NK cells, and that this effect was mediated by engagement of cellular CD81 by HCV-virion displayed E2. In contrast, NK-production of IL-8 was increased in the presence of HCV. The cytokines produced by IL-12 activated NK cells strongly reduced the establishment of productive HCV infection. Importantly, NK-cell derived cytokines secreted in the presence of HCVcc showed a diminished antiviral effect that correlated with IFN-gamma reduction, while IL-8 concentrations had no impact on HCV infectivity.
  
  
  CONCLUSIONS
  Exposure to HCVcc modulates the pattern of cytokines produced by NK cells, leading to reduced antiviral activity.
authors.affiliation: Department of Microbial Molecular Biology, Novartis Vaccines and Diagnostics, Siena, Italy. scrotta@nimr.mrc.ac.uk
authors.forename: Stefania
authors.initials: S
authors.lastname: Crotta
authors.forename: Michela
authors.initials: M
authors.lastname: Brazzoli
authors.forename: Diego
authors.initials: D
authors.lastname: Piccioli
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Valiante
authors.forename: Andreas
authors.initials: A
authors.lastname: Wack
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D002478:Cells, Cultured; D003432:Cross-Linking Reagents; D016207:Cytokines / Q000096:biosynthesis*; D016174:Hepacivirus / Q000276:immunology* / Q000472:pathogenicity*; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000821:virology*; D008213:Lymphocyte Activation; D009500:Neutralization Tests; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins / Q000276:immunology
chemical_list: D015703:Antigens, CD; C554798:CD81 protein, human; C508606:CXCL8 protein, human; D003432:Cross-Linking Reagents; D016207:Cytokines; D016209:Interleukin-8; D011994:Recombinant Proteins; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus; D018664:Interleukin-12; D007371:Interferon-gamma