title: Apolipoprotein E, but Not Apolipoprotein B, Is Essential for Efficient Cell-to-Cell Transmission of Hepatitis C Virus.
abstract: Hepatitis C virus (HCV) infects hepatocytes through two different routes: (i) cell-free particle diffusion followed by engagement with specific cellular receptors and (ii) cell-to-cell direct transmission mediated by mechanisms not well defined yet. HCV exits host cells in association with very-low-density lipoprotein (VLDL) components. VLDL particles contain apolipoproteins B (ApoB) and E (ApoE), which are required for viral assembly and/or infectivity. Based on these precedents, we decided to study whether these VLDL components participate in HCV cell-to-cell transmission in vitro. We observed that cell-to-cell viral spread was compromised after ApoE interference in donor but not in acceptor cells. In contrast, ApoB knockdown in either donor or acceptor cells did not impair cell-to-cell viral transmission. Interestingly, ApoB participated in the assembly of cell-free infective virions, suggesting a differential regulation of cell-to-cell and cell-free HCV infection. This study identifies host-specific factors involved in these distinct routes of infection that may unveil new therapeutic targets and advance our understanding of HCV pathogenesis.
  
  
  OBJECTIVE
  This work demonstrates that cell-to-cell transmission of HCV depends on ApoE but not ApoB. The data also indicate that ApoB is required for the assembly of cell-free infective particles, strongly suggesting the existence of mechanisms involving VLDL components that differentially regulate cell-free and cell-to-cell HCV transmission. These data clarify some of the questions regarding the role of VLDL in HCV pathogenesis and the transmission of the virus cell to cell as a possible mechanism of immune evasion and open the door to therapeutic intervention.
authors.affiliation: Molecular Biology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Virgínia
authors.initials: V
authors.lastname: Gondar
authors.affiliation: Molecular Biology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Molina-Jiménez
authors.affiliation: Laboratory of Primate Model, Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hishiki
authors.affiliation: CIBERehd, Instituto de Salud Carlos III, Madrid, Spain Liver Unit, Hospital Universitario de la Princesa (IP), Madrid, Spain.
authors.forename: Luisa
authors.initials: L
authors.lastname: García-Buey
authors.affiliation: CIBERehd, Instituto de Salud Carlos III, Madrid, Spain Liver Unit, Institut D'Investigacions Biomèdics August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain.
authors.forename: George
authors.initials: G
authors.lastname: Koutsoudakis
authors.affiliation: Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan.
authors.forename: Kunitada
authors.initials: K
authors.lastname: Shimotohno
authors.affiliation: Molecular Biology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain CIBERehd, Instituto de Salud Carlos III, Madrid, Spain igb2005@med.cornell.edu pedro.majano@salud.madrid.org.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Benedicto
authors.affiliation: Molecular Biology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain CIBERehd, Instituto de Salud Carlos III, Madrid, Spain igb2005@med.cornell.edu pedro.majano@salud.madrid.org.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Majano
mesh_terms: D001055:Apolipoproteins B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001057:Apolipoproteins E / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002474:Cell-Free System; D055785:Gene Knockdown Techniques; D016174:Hepacivirus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D006526:Hepatitis C / Q000378:metabolism / Q000635:transmission* / Q000821:virology; D022781:Hepatocytes / Q000378:metabolism* / Q000821:virology*; D054884:Host-Pathogen Interactions / Q000502:physiology; D006801:Humans; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008954:Models, Biological; D019065:Virus Assembly / Q000502:physiology
chemical_list: D001055:Apolipoproteins B; D001057:Apolipoproteins E; D008079:Lipoproteins, VLDL