Potential conflict of interest: Nothing to report.
An alpaca nanobody inhibits hepatitis C virus entry and cell-to-cell transmission
Article first published online: 30 JUL 2013
© 2013 by the American Association for the Study of Liver Diseases
Volume 58, Issue 3, pages 932–939, September 2013
How to Cite
Tarr, A. W., Lafaye, P., Meredith, L., Damier-Piolle, L., Urbanowicz, R. A., Meola, A., Jestin, J.-L., Brown, R. J. P., McKeating, J. A., Rey, F. A., Ball, J. K. and Krey, T. (2013), An alpaca nanobody inhibits hepatitis C virus entry and cell-to-cell transmission. Hepatology, 58: 932–939. doi: 10.1002/hep.26430
This work was funded by grants from the UK Medical Research Council, ANRS, and recurrent funding from Institut Pasteur, CNRS, and Merck-Serono (to F. A. R.).
- Issue published online: 29 AUG 2013
- Article first published online: 30 JUL 2013
- Accepted manuscript online: 28 MAR 2013 08:05AM EST
- Manuscript Accepted: 25 MAR 2013
- Manuscript Received: 6 FEB 2013
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)