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Journal of Virology, November 2006, p. 10579-10590, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.00941-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Viral and Cellular Determinants of the Hepatitis C Virus Envelope-Heparan Sulfate Interaction{triangledown}

Heidi Barth,1 Eva K. Schnober,1 Fuming Zhang,2 Robert J. Linhardt,2 Erik Depla,3 Bertrand Boson,4 Francois-Loic Cosset,4 Arvind H. Patel,5 Hubert E. Blum,1 and Thomas F. Baumert1,6*

Department of Medicine II, University of Freiburg, Freiburg, Germany,1 Department of Biology and Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York,2 Innogenetics N.V., Ghent, Belgium,3 INSERM U412, Ecole Normale Supérieure, Lyon, France,4 MRC Virology Unit, Glasgow, United Kingdom,5 INSERM Unité U748, Université Louis Pasteur, Strasbourg, France6

Received 9 May 2006/ Accepted 9 August 2006

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.

* Corresponding author. Mailing address: Department of Medicine II, University of Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany. Phone: 49-761-270-3401. Fax: 49-761-270-3259. E-mail: Thomas.Baumert{at}uniklinik-freiburg.de.

{triangledown} Published ahead of print on 23 August 2006.

Journal of Virology, November 2006, p. 10579-10590, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.00941-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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