Apolipoprotein E Mediates Attachment of Clinical Hepatitis C Virus to Hepatocytes by Binding to Cell Surface Heparan Sulfate Proteoglycan Receptors.docVIP

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Apolipoprotein E Mediates Attachment of Clinical Hepatitis C Virus to Hepatocytes by Binding to Cell Surface Heparan Sulfate Proteoglycan Receptors.doc

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Apolipoprotein E Mediates Attachment of Clinical Hepatitis C Virus to Hepatocytes by Binding to Cell Surface Heparan Sulfate Proteoglycan Receptors

ApolipoproteinEMediatesAttachmentofClinical HepatitisCVirustoHepatocytesbyBindingtoCell SurfaceHeparanSulfateProteoglycanReceptors JieyunJiang1,XianfangWu2,HengliTang2,GuangxiangLuo1,3,4* 1Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America, 2DepartmentofBiologicalScience,TheFloridaStateUniversity,Tallahassee,Florida,UnitedStatesofAmerica,3DepartmentofMicrobiology,UniversityofAlabamaat Birmingham SchoolofMedicine,Birmingham,Alabama,UnitedStatesofAmerica,4DepartmentofMicrobiology,PekingUniversityCollegeofBasicMedicalSciences, Beijing,China Abstract Ourpreviousstudiesdemonstratedthatthecellculture-grownhepatitisCvirusofgenotype2a(HCVcc)usesapolipoprotein E(apoE)tomediateitsattachmenttothesurfaceofhumanhepatomaHuh-7.5cells.ApoEmediatesHCVattachmentby bindingtothecellsurfaceheparansulfate(HS)whichiscovalentlyattachedtothecoreproteinsofproteoglycans(HSPGs). Inthepresentstudy,wefurtherdeterminedthephysiologicalimportanceofapoEandHSPGsintheHCVattachmentusing aclinicalHCVofgenotype1b(HCV1b)obtainedfromhepatitisCpatientsandhumanembryonicstemcell-differentiated hepatocyte-like cells (DHHs). DHHs were found to resemble primary human hepatocytes. Similar to HCVcc, HCV1b was found to attach to the surface of DHHs by the apoE-mediated binding to the cell surface HSPGs. The apoE-specific monoclonalantibody,purifiedHSPGs,andheparinwereallabletoefficientlyblockHCV1battachmenttoDHHs.Similarly, the removal of heparan sulfate from cell surface by treatment with heparinase suppressed HCV1b attachment to DHHs. More significantly, HCV1b attachment was potently inhibited by a synthetic peptide derived from the apoE receptor- bindingregionaswellasbyanHSPG-bindingpeptide.Likewise,theHSPG-bindingpeptidepreventedapoEfrombindingto heparin in a dose-dependent manner, as determined by an invitro heparin pull-down assay. Collectively, these findings demonstratethatHSPGsserveasmajorHCVattachmentre