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Background & Aims: Hepatitis C virus (HCV)-induced end-stage liver disease is currently the major indication for liver transplantation in the Western world. After transplantation, the donor liver almost inevitably becomes infected by the circulating virus and disease progression is accelerated in immune suppressed transplant patients. The current standard therapy, based on pegylated interferon and ribavirin, induces severe side effects and is often ineffective in this population. Therefore, new strategies to prevent graft re-infection are urgently needed. We have previously shown that monoclonal antibodies (mAbs) against the HCV co-receptor scavenger receptor class B type I (SR-BI/Cla1) inhibit infection by different HCV genotypes in cell culture., Methods: Using phage display libraries, we have generated a large set of novel human mAbs against SR-BI and evaluated their effectiveness in preventing HCV infection and direct cell-to-cell spread in vitro and in vivo using uPA-SCID mice with a humanized liver., Results: Eleven human monoclonal antibodies were generated that specifically recognize SR-BI. Two antibodies, mAb8 and mAb151, displayed the highest binding and inhibitory properties and also interfered with direct cell-to-cell spread in vitro. Studies in humanized mice showed that both antibodies were capable of preventing HCV infection and could block intrahepatic spread and virus amplification when administered 3 days after infection. Interestingly, anti-SR-BI therapy was effective against an HCV variant that escaped the control of the adaptive immune response in a liver transplant patient., Conclusions: The anti-SR-BI mAbs generated in this study may represent novel therapeutic tools to prevent HCV re-infection of liver allografts., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma. Preventive modalities are absent and the current antiviral treatment is limited by resistance, toxicity, and high costs. Viral entry is required for initiation, spread, and maintenance of infection, and thus is a promising target for antiviral therapy. HCV entry is a highly orchestrated process involving viral and host cell factors. These include the viral envelope glycoproteins E1 and E2, CD81, scavenger receptor BI, and tight junction proteins claudin-1 and occludin. Recent studies in preclinical models and HCV-infected patients have demonstrated that the virus has developed multiple strategies to escape host immune responses during viral entry. These include evasion from neutralizing antibodies and viral spread by cell-cell transmission. These challenges have to be taken into account for the design of efficient antiviral strategies. Thus, a detailed understanding of the mechanisms of viral entry and escape is a prerequisite to define viral and cellular targets and develop novel preventive and therapeutic antivirals. This review summarizes the current knowledge about the molecular mechanisms of HCV entry into hepatocytes, highlights novel targets and reviews the current preclinical and clinical development of compounds targeting entry. Proof-of-concept studies suggest that HCV entry inhibitors are a novel and promising class of antivirals widening the preventive and therapeutic arsenal against HCV infection., (Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)