2.50
Hdl Handle:
http://hdl.handle.net/10033/305703
Title:
An alpaca nanobody inhibits hepatitis C virus entry and cell-to-cell transmission.
Authors:
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.
Affiliation:
School of Molecular Medical Sciences, The University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom.
Citation:
An alpaca nanobody inhibits hepatitis C virus entry and cell-to-cell transmission. 2013, 58 (3):932-9 Hepatology
Journal:
Hepatology (Baltimore, Md.)
Issue Date:
Sep-2013
URI:
http://hdl.handle.net/10033/305703
DOI:
10.1002/hep.26430
PubMed ID:
23553604
Type:
Article
Language:
en
ISSN:
1527-3350
Appears in Collections:
publications of the department experimental Virology([TC]EVIR)

Full metadata record

DC FieldValue Language
dc.contributor.authorTarr, Alexander Wen
dc.contributor.authorLafaye, Pierreen
dc.contributor.authorMeredith, Lukeen
dc.contributor.authorDamier-Piolle, Laurenceen
dc.contributor.authorUrbanowicz, Richard Aen
dc.contributor.authorMeola, Annalisaen
dc.contributor.authorJestin, Jean-Lucen
dc.contributor.authorBrown, Richard J Pen
dc.contributor.authorMcKeating, Jane Aen
dc.contributor.authorRey, Felix Aen
dc.contributor.authorBall, Jonathan Ken
dc.contributor.authorKrey, Thomasen
dc.date.accessioned2013-11-22T15:45:21Z-
dc.date.available2013-11-22T15:45:21Z-
dc.date.issued2013-09-
dc.identifier.citationAn alpaca nanobody inhibits hepatitis C virus entry and cell-to-cell transmission. 2013, 58 (3):932-9 Hepatologyen
dc.identifier.issn1527-3350-
dc.identifier.pmid23553604-
dc.identifier.doi10.1002/hep.26430-
dc.identifier.urihttp://hdl.handle.net/10033/305703-
dc.description.abstractSevere 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.en
dc.language.isoenen
dc.rightsArchived with thanks to Hepatology (Baltimore, Md.)en
dc.titleAn alpaca nanobody inhibits hepatitis C virus entry and cell-to-cell transmission.en
dc.typeArticleen
dc.contributor.departmentSchool of Molecular Medical Sciences, The University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom.en
dc.identifier.journalHepatology (Baltimore, Md.)en

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