Projects per year
Abstract
UNLABELLED: 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.
Original language | English |
---|---|
Pages (from-to) | 932-9 |
Number of pages | 8 |
Journal | Hepatology |
Volume | 58 |
Issue number | 3 |
DOIs | |
Publication status | Published - Sept 2013 |
Keywords
- Amino Acid Sequence
- Animals
- Camelids, New World
- Cell Communication
- Cell Line, Tumor
- Cells, Cultured
- Epitope Mapping
- Epitopes
- Genotype
- Hepacivirus
- Hepatitis C
- Humans
- Liver
- Molecular Sequence Data
- Single-Domain Antibodies
- Viral Envelope Proteins
- Virus Internalization
Fingerprint
Dive into the research topics of 'An alpaca nanobody inhibits hepatitis C virus entry and cell-to-cell transmission'. Together they form a unique fingerprint.Projects
- 2 Finished
-
The Role of Hepatitis C Virus Glycoprotein-Receptor Polymorphism in Viral Pathogenesis
McKeating, J.
1/01/12 → 30/06/17
Project: Research Councils
-
Mechanisms of Hepatitis C Virus Induced Hepatocyte Injury
McKeating, J. & Balfe, P.
1/10/09 → 30/09/12
Project: Research Councils