Viral and cellular determinants of the hepatitis C virus envelope-heparan sulfate interaction.
Cellular binding and entry of hepatitis C virus (HCV) are the first steps of viral infection and represent a major target for antiviral antibodies and novel therapeutic strategies. We have recently demonstrated that heparan sulfate (HS) plays a key role in the binding of HCV envelope glycoprotein E2 to target cells (Barth et al., J. Biol. Chem. 278:41003-41012, 2003). In this study, we characterized the HCV-HS interaction and analyzed its inhibition by antiviral host immune responses. Using recombinant envelope glycoproteins, virus-like particles, and HCV pseudoparticles as model systems for the early steps of viral infection, we mapped viral and cellular determinants of HCV-HS interaction. HCV-HS binding required a specific HS structure that included N-sulfo groups and a minimum of 10 to 14 saccharide subunits. HCV envelope binding to HS was mediated by four viral epitopes overlapping the E2 hypervariable region 1 and E2-CD81 binding domains. In functional studies using HCV pseudoparticles, we demonstrate that HCV binding and entry are specifically inhibited by highly sulfated HS. Finally, HCV-HS binding was markedly inhibited by antiviral antibodies derived from HCV-infected individuals. In conclusion, our results demonstrate that binding of the viral envelope to a specific HS configuration represents an important step for the initiation of viral infection and is a target of antiviral host immune responses in vivo. Mapping of viral and cellular determinants of HCV-HS interaction sets the stage for the development of novel HS-based antiviral strategies targeting viral attachment and entry.
Barth
Heidi
H
Department of Medicine II, University of Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany.
Schnober
Eva K
EK
Zhang
Fuming
F
Linhardt
Robert J
RJ
Depla
Erik
E
Boson
Bertrand
B
Cosset
Francois-Loic
FL
Patel
Arvind H
AH
Blum
Hubert E
HE
Baumert
Thomas F
TF
D000818:Animals; D000914:Antibodies, Viral; D000956:Antigens, Viral; D001665:Binding Sites; D002460:Cell Line; D018604:Epitope Mapping; D006367:HeLa Cells; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology*; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism*; D019698:Hepatitis C, Chronic / Q000209:etiology / Q000276:immunology / Q000821:virology; D006801:Humans; D051379:Mice; D011485:Protein Binding; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020349:Surface Plasmon Resonance; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D014774:Virulence
D000914:Antibodies, Viral; D000956:Antigens, Viral; D006497:Heparan Sulfate; D011994:Recombinant Proteins; D014759:Viral Envelope Proteins