title: Hepatitis C virus infects the endothelial cells of the blood-brain barrier.
abstract: OBJECTIVE
  Hepatitis C virus (HCV) infection leads to progressive liver disease and is associated with a variety of extrahepatic syndromes, including central nervous system (CNS) abnormalities. However, it is unclear whether such cognitive abnormalities are a function of systemic disease, impaired hepatic function, or virus infection of the CNS.
  
  
  METHODS
  We measured levels of HCV RNA and expression of the viral entry receptor in brain tissue samples from 10 infected individuals (and 3 uninfected individuals, as controls) and human brain microvascular endothelial cells by using quantitative polymerase chain reaction and immunochemical and confocal imaging analyses. HCV pseudoparticles and cell culture-derived HCV were used to study the ability of endothelial cells to support viral entry and replication.
  
  
  RESULTS
  Using quantitative polymerase chain reaction, we detected HCV RNA in brain tissue of infected individuals at significantly lower levels than in liver samples. Brain microvascular endothelia and brain endothelial cells expressed all of the recognized HCV entry receptors. Two independently derived brain endothelial cell lines, hCMEC/D3 and HBMEC, supported HCV entry and replication. These processes were inhibited by antibodies against the entry factors CD81, scavenger receptor BI, and claudin-1; by interferon; and by reagents that inhibit NS3 protease and NS5B polymerase. HCV infection promotes endothelial permeability and cellular apoptosis.
  
  
  CONCLUSIONS
  Human brain endothelial cells express functional receptors that support HCV entry and replication. Virus infection of the CNS might lead to HCV-associated neuropathologies.
authors.affiliation: Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England.
authors.forename: Nicola F
authors.initials: NF
authors.lastname: Fletcher
authors.forename: Garrick K
authors.initials: GK
authors.lastname: Wilson
authors.forename: Jacinta
authors.initials: J
authors.lastname: Murray
authors.forename: Ke
authors.initials: K
authors.lastname: Hu
authors.forename: Andrew
authors.initials: A
authors.lastname: Lewis
authors.forename: Gary M
authors.initials: GM
authors.lastname: Reynolds
authors.forename: Zania
authors.initials: Z
authors.lastname: Stamataki
authors.forename: Luke W
authors.initials: LW
authors.lastname: Meredith
authors.forename: Ian A
authors.initials: IA
authors.lastname: Rowe
authors.forename: Guangxiang
authors.initials: G
authors.lastname: Luo
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Lopez-Ramirez
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
authors.forename: Babette
authors.initials: B
authors.lastname: Weksler
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.forename: Kwang Sik
authors.initials: KS
authors.lastname: Kim
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Romero
authors.forename: Catherine
authors.initials: C
authors.lastname: Jopling
authors.forename: Susan
authors.initials: S
authors.lastname: Morgello
authors.forename: Peter
authors.initials: P
authors.lastname: Balfe
authors.forename: Jane A
authors.initials: JA
authors.lastname: McKeating
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D002199:Capillary Permeability; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D005260:Female; D057809:HEK293 Cells; D016174:Hepacivirus / Q000235:genetics / Q000472:pathogenicity*; D006526:Hepatitis C / Q000150:complications / Q000401:mortality / Q000821:virology*; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000821:virology; D008297:Male; D018613:Microscopy, Confocal; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D008875:Middle Aged; D012367:RNA, Viral / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011991:Receptors, Virus / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism; D014771:Virion / Q000378:metabolism; D053586:Virus Internalization; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral; D011991:Receptors, Virus; D014759:Viral Envelope Proteins