heparitin-sulfate and Hepatitis-C--Chronic

An 84-year-old woman with hepatitis C virus-related cirrhosis, hepatocellular carcinoma and atrial fibrillation, who presented with hematemesis, was initially treated with endoscopic variceal ligation (EVL) for an esophageal varix hemorrhage. However, computed tomography (CT) upon admission had revealed portal vein thrombosis, despite having received warfarin for existing atrial fibrillation. We subsequently initiated a 2-week treatment with danaparoid;warfarin being discontinued in order to reduce the risk of re-hemorrhage. A follow-up CT after treatment revealed complete reduction of the portal vein thrombosis. This is the first successful report of danaparoid use in the treatment of portal vein thrombosis that developed in a patient who had received warfarin.

Topics: Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Chondroitin Sulfates; Dermatan Sulfate; Female; Heparitin Sulfate; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Portal Vein; Thrombosis; Warfarin

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.

Topics: Animals; Antibodies, Viral; Antigens, Viral; Binding Sites; Cell Line; Epitope Mapping; HeLa Cells; Hepacivirus; Heparitin Sulfate; Hepatitis C, Chronic; Humans; Mice; Protein Binding; Recombinant Proteins; Surface Plasmon Resonance; Viral Envelope Proteins; Virulence