An alpaca nanobody inhibits hepatitis C virus entry and cell-to-cell transmission

Tarr, Alexander W.; Lafaye, Pierre; Meredith, Luke; Damier-Piolle, Laurence; Urbanowicz, Richard A.; Meola, Annalisa; Jestin, Jean Luc; Brown, Richard J.P.; Mckeating, Jane A.; Rey, Felix A.; Ball, Jonathan K.; Krey, Thomas

Abstract

Severe liver disease caused by chronic hepatitis C virus is the major indication for liver transplantation. Despite recent advances in antiviral therapy, drug toxicity and unwanted side effects render effective treatment in liver-transplanted patients a challenging task. Virus-specific therapeutic antibodies are generally safe and well-tolerated, but their potential in preventing and treating hepatitis C virus (HCV) infection has not yet been realized due to a variety of issues, not least high production costs and virus variability. Heavy-chain antibodies or nanobodies, produced by camelids, represent an exciting antiviral approach; they can target novel highly conserved epitopes that are inaccessible to normal antibodies, and they are also easy to manipulate and produce. We isolated four distinct nanobodies from a phage-display library generated from an alpaca immunized with HCV E2 glycoprotein. One of them, nanobody D03, recognized a novel epitope overlapping with the epitopes of several broadly neutralizing human monoclonal antibodies. Its crystal structure revealed a long complementarity determining region (CD3) folding over part of the framework that, in conventional antibodies, forms the interface between heavy and light chain. D03 neutralized a panel of retroviral particles pseudotyped with HCV glycoproteins from six genotypes and authentic cell culture-derived particles by interfering with the E2-CD81 interaction. In contrast to some of the most broadly neutralizing human anti-E2 monoclonal antibodies, D03 efficiently inhibited HCV cell-to-cell transmission. Conclusion: This is the first description of a potent and broadly neutralizing HCV-specific nanobody representing a significant advance that will lead to future development of novel entry inhibitors for the treatment and prevention of HCV infection and help our understanding of HCV cell-to-cell transmission. (Hepatology 2013;53:932-939). © 2013 by the American Association for the Study of Liver Diseases.

Citation

Tarr, A. W., Lafaye, P., Meredith, L., Damier-Piolle, L., Urbanowicz, R. A., Meola, A., Jestin, J. L., Brown, R. J., Mckeating, J. A., Rey, F. A., Ball, J. K., & Krey, T. (2013). An alpaca nanobody inhibits hepatitis C virus entry and cell-to-cell transmission. Hepatology, 58(3), 932-939. https://doi.org/10.1002/hep.26430

• Journal Article Type: Article
• Acceptance Date: Mar 25, 2013
• Online Publication Date: Jul 30, 2013
• Publication Date: 2013-09
• Deposit Date: Nov 9, 2022
• Journal: Hepatology
• Print ISSN: 0270-9139
• Electronic ISSN: 1527-3350
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 58
• Issue: 3
• Pages: 932-939
• DOI: https://doi.org/10.1002/hep.26430
• Public URL: https://nottingham-repository.worktribe.com/output/3129463
• Publisher URL: https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.26430