title: Hepatitis C virus targets the T cell secretory machinery as a mechanism of immune evasion.
abstract: T cell activation and the resultant production of interleukin (IL-2) is a central response of the adaptive immune system to pathogens, such as hepatitis C virus (HCV). HCV uses several mechanisms to evade both the innate and adaptive arms of the immune response. Here we demonstrate that liver biopsy specimens from individuals infected with HCV had significantly lower levels of IL-2 compared with those with other inflammatory liver diseases. Cell culture-grown HCV particles inhibited the production of IL-2 by normal peripheral blood mononuclear cells, as did serum from HCV-infected patients. This process was mediated by the interaction of HCV envelope protein E2 with tetraspanin CD81 coreceptor. HCV E2 attenuated IL-2 production at the level of secretion and not transcription by targeting the translocation of protein kinase C beta (PKCβ), which is essential for IL-2 secretion, to lipid raft microdomains. The lipid raft disruptor methyl-β-cyclodextrin reversed HCV E2-mediated inhibition of IL-2 secretion, but not in the presence of a PKCβ-selective inhibitor. HCV E2 further inhibited the secretion of other cytokines, including interferon-γ.
  
  
  CONCLUSIONS
  These data suggest that HCV E2-mediated disruption of the association of PKCβ with the cellular secretory machinery represents a novel mechanism for HCV to evade the human immune response and to establish persistent infection.
authors: Department of Clinical Medicine and Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
authors: Danijela
authors: D
authors: Petrovic
authors: Zania
authors: Z
authors: Stamataki
authors: Eugene
authors: E
authors: Dempsey
authors: Lucy
authors: L
authors: Golden-Mason
authors: Michael
authors: M
authors: Freeley
authors: Derek
authors: D
authors: Doherty
authors: David
authors: D
authors: Prichard
authors: Catherine
authors: C
authors: Keogh
authors: Jennifer
authors: J
authors: Conroy
authors: Siobhan
authors: S
authors: Mitchell
authors: Yuri
authors: Y
authors: Volkov
authors: Jane A
authors: JA
authors: McKeating
authors: Cliona
authors: C
authors: O'Farrelly
authors: Dermot
authors: D
authors: Kelleher
authors: Aideen
authors: A
authors: Long
mesh_terms: D056704:Adaptive Immunity / Q000502:physiology*; D015703:Antigens, CD / Q000378:metabolism; D001706:Biopsy; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016174:Hepacivirus / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D057131:Immune Evasion / Q000502:physiology*; D007113:Immunity, Innate / Q000502:physiology*; D007376:Interleukin-2 / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D021962:Membrane Microdomains / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C554798:CD81 protein, human; D007376:Interleukin-2; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus; D011493:Protein Kinase C; D064546:Protein Kinase C beta