title: Apolipoprotein E on hepatitis C virion facilitates infection through interaction with low-density lipoprotein receptor.
abstract: Hepatitis C virus (HCV) infection is a major cause of liver disease. HCV associates with host apolipoproteins and enters hepatocytes through complex processes involving some combination of CD81, claudin-1, occludin, and scavenger receptor BI. Here we show that infectious HCV resembles very low density lipoprotein (VLDL) and that entry involves co-receptor function of the low-density lipoprotein receptor (LDL-R). Blocking experiments demonstrate that beta-VLDL itself or anti-apolipoprotein E (apoE) antibody can block HCV entry. Knockdown of the LDL-R by treatment with 25-hydroxycholesterol or siRNA ablated ligand uptake and reduced HCV infection of cells, whereas infection was rescued upon cell ectopic LDL-R expression. Analyses of gradient-fractionated HCV demonstrate that apoE is associated with HCV virions exhibiting peak infectivity and dependence upon the LDL-R for cell entry. Our results define the LDL-R as a cooperative HCV co-receptor that supports viral entry and infectivity through interaction with apoE ligand present in an infectious HCV/lipoprotein complex comprising the virion. Disruption of HCV/LDL-R interactions by altering lipoprotein metabolism may therefore represent a focus for future therapy.
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Owen
authors.forename: Hua
authors.initials: H
authors.lastname: Huang
authors.forename: Jin
authors.initials: J
authors.lastname: Ye
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
mesh_terms: D001057:Apolipoproteins E / Q000302:isolation & purification / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D016174:Hepacivirus / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D011485:Protein Binding; D011973:Receptors, LDL / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011991:Receptors, Virus / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053585:Virus Attachment; D053586:Virus Internalization
chemical_list: D001057:Apolipoproteins E; D011973:Receptors, LDL; D011991:Receptors, Virus