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

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

Research output: Contribution to journalArticlepeer-review

53 Citations (Scopus)

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 languageEnglish
Pages (from-to)932-9
Number of pages8
JournalHepatology
Volume58
Issue number3
DOIs
Publication statusPublished - Sep 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

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