title: Hepatitis C virus targets DC-SIGN and L-SIGN to escape lysosomal degradation.
abstract: Hepatitis C virus (HCV) is a major health problem. However, the mechanism of hepatocyte infection is largely unknown. We demonstrate that the dendritic cell (DC)-specific C-type lectin DC-SIGN and its liver-expressed homologue L-SIGN/DC-SIGNR are important receptors for HCV envelope glycoproteins E1 and E2. Mutagenesis analyses demonstrated that both HCV E1 and E2 bind the same binding site on DC-SIGN as the pathogens human immunodeficiency virus type 1 (HIV-1) and mycobacteria, which is distinct from the cellular ligand ICAM-3. HCV virus-like particles are efficiently captured and internalized by DCs through binding of DC-SIGN. Antibodies against DC-SIGN specifically block HCV capture by both immature and mature DCs, demonstrating that DC-SIGN is the major receptor on DCs. Interestingly, internalized HCV virus-like particles were targeted to nonlysosomal compartments within immature DCs, where they are protected from lysosomal degradation in a manner similar to that demonstrated for HIV-1. Lewis X antigen, another ligand of DC-SIGN, was internalized to lysosomes, demonstrating that the internalization pathway of DC-SIGN-captured ligands may depend on the structure of the ligand. Our results suggest that HCV may target DC-SIGN to "hide" within DCs and facilitate viral dissemination. L-SIGN, expressed by THP-1 cells, internalized HCV particles into similar nonlysosomal compartments, suggesting that L-SIGN on liver sinusoidal endothelial cells may capture HCV from blood and transmit it to hepatocytes, the primary target for HCV. We therefore conclude that both DCs and liver sinusoidal endothelial cells may act as reservoirs for HCV and that the C-type lectins DC-SIGN and L-SIGN, as important HCV receptors, may represent a molecular target for clinical intervention in HCV infection.
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Irene S
authors.initials: IS
authors.lastname: Ludwig
authors.forename: Annemarie N
authors.initials: AN
authors.lastname: Lekkerkerker
authors.forename: Erik
authors.initials: E
authors.lastname: Depla
authors.forename: Fons
authors.initials: F
authors.lastname: Bosman
authors.forename: René J P
authors.initials: RJ
authors.lastname: Musters
authors.forename: Stany
authors.initials: S
authors.lastname: Depraetere
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Kooyk
authors.forename: Teunis B H
authors.initials: TB
authors.lastname: Geijtenbeek
mesh_terms: D015815:Cell Adhesion Molecules / Q000502:physiology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000502:physiology; D011992:Endosomes / Q000821:virology; D042783:Endothelial Cells / Q000821:virology; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D037181:Lectins, C-Type / Q000502:physiology*; D008247:Lysosomes / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000502:physiology*; D014759:Viral Envelope Proteins / Q000378:metabolism; D014771:Virion / Q000502:physiology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D014759:Viral Envelope Proteins; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C433029:CLEC4M protein, human; C087035:E1 protein, Hepatitis C virus; C091015:glycoprotein E2, Hepatitis C virus