Viral and Cellular Determinants of Hepatitis C Virus Envelope-Heparan Sulfate Interaction

Barth, Heidi
Schnober, Eva K.
Zhang, Fuming
Linhardt, Robert J.
Depla, Erik
Boson, Bertrand
Cosset, Francois Loic
Patel, Arvind H.
Blum, Hubert E.
Baumert, Thomas F.
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Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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Viral and Cellular Determinants of Hepatitis C Virus Envelope-Heparan Sulfate Interaction, H. Barth, E. K. Schnober, F. Zhang, R. J. Linhardt, E. Depla, B. Boson, F.-L. Cosset, A. Patel, H. E. Blum, T. F. Baumert, Journal of Virology, 80, 10579-10590, 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.
Journal of Virology, 80, 10579-10590
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The Linhardt Research Labs.
The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
The Linhardt Research Labs Online Collection
Rensselaer Polytechnic Institute, Troy, NY
Journal of Virology