title: Hepatitis C virus utilizes VLDLR as a novel entry pathway.
abstract: Various host factors are involved in the cellular entry of hepatitis C virus (HCV). In addition to the factors previously reported, we discovered that the very-low-density lipoprotein receptor (VLDLR) mediates HCV entry independent of CD81. Culturing Huh7.5 cells under hypoxic conditions significantly increased HCV entry as a result of the expression of VLDLR, which was not expressed under normoxic conditions in this cell line. Ectopic VLDLR expression conferred susceptibility to HCV entry of CD81-deficient Huh7.5 cells. Additionally, VLDLR-mediated HCV entry was not affected by the knockdown of cellular factors known to act as HCV receptors or HCV entry factors. Because VLDLR is expressed in primary human hepatocytes, our results suggest that VLDLR functions in vivo as an HCV receptor independent of canonical CD81-mediated HCV entry.
authors.affiliation: Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, 272-8516 Japan; lbujino@hospk.ncgm.go.jp lbshimotohno@hospk.ncgm.go.jp.
authors.forename: Saneyuki
authors.initials: S
authors.lastname: Ujino
authors.affiliation: Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, 272-8516 Japan;
authors.forename: Hironori
authors.initials: H
authors.lastname: Nishitsuji
authors.affiliation: Laboratory of Primate Model, Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University, Kyoto, 606-8507 Japan;
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hishiki
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, 160-8582 Japan;
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sugiyama
authors.affiliation: Research Institute, Chiba Institute of Technology, Tsudanuma, Narashino, Chiba 275-0016 Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takaku
authors.affiliation: Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, 272-8516 Japan; lbujino@hospk.ncgm.go.jp lbshimotohno@hospk.ncgm.go.jp.
authors.forename: Kunitada
authors.initials: K
authors.lastname: Shimotohno
mesh_terms: D000693:Anaerobiosis; D000818:Animals; D002460:Cell Line; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000821:virology*; D022781:Hepatocytes / Q000821:virology*; D006801:Humans; D008079:Lipoproteins, VLDL / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D062793:Occludin / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology*; D011991:Receptors, Virus / Q000235:genetics / Q000502:physiology*; D060225:Tetraspanin 28 / Q000235:genetics / Q000502:physiology; D053586:Virus Internalization
chemical_list: D008079:Lipoproteins, VLDL; C568985:OCLN protein, human; D062793:Occludin; D011973:Receptors, LDL; D011991:Receptors, Virus; D060225:Tetraspanin 28; C036053:VLDL receptor
keywords: CD81; VLDLR; hepatitis C virus; hypoxia; virus entry