DC-SIGN and L-SIGN are high affinity binding receptors for hepatitis C virus glycoprotein E2.
The hepatitis C virus (HCV) genome codes for highly mannosylated envelope proteins, which are naturally retained in the endoplasmic reticulum. We found that the HCV envelope glycoprotein E2 binds the dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) and the related liver endothelial cell lectin L-SIGN through high-mannose N-glycans. Competing ligands such as mannan and an antibody directed against the carbohydrate recognition domains (CRD) abrogated binding. While no E2 interaction with distant monomeric CRDs on biosensor chips could be detected, binding is observed if CRDs are closely seeded (Kd = 48 nm) and if the CRD is part of the oligomeric-soluble extracellular domain of DC-SIGN (Kd = 30 nm). The highest affinity is seen for plasma membrane-expressed DC-SIGN and L-SIGN (Kd = 3 and 6 nm, respectively). These results indicate that several high-mannose N-glycans in a structurally defined cluster on E2 bind to several subunits of the oligomeric lectin CRD. High affinity interaction of viral glycoproteins with oligomeric lectins might represent a strategy by which HCV targets to and concentrates in the liver and infects dendritic cells.
Lozach
Pierre-Yves
PY
Unité d'Immunologie Virale, Institut Pasteur, 28, rue du Dr. Roux, 75015 Paris, France.
Lortat-Jacob
Hugues
H
de Lacroix de Lavalette
Agnès
A
Staropoli
Isabelle
I
Foung
Steven
S
Amara
Ali
A
Houles
Corinne
C
Fieschi
Frank
F
Schwartz
Olivier
O
Virelizier
Jean-Louis
JL
Arenzana-Seisdedos
Fernando
F
Altmeyer
Ralf
R
D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D017931:DNA Primers; D037181:Lectins, C-Type / Q000378:metabolism*; D008358:Mannose / Q000378:metabolism; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000378:metabolism*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D017931:DNA Primers; D037181:Lectins, C-Type; D008358:Mannose; D011956:Receptors, Cell Surface; D014759:Viral Envelope Proteins; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C091015:glycoprotein E2, Hepatitis C virus