Structural basis of HCV neutralization by human monoclonal antibodies resistant to viral neutralization escape.

The high mutation rate of hepatitis C virus allows it to rapidly evade the humoral immune response. However, certain epitopes in the envelope glycoproteins cannot vary without compromising virus viability. Antibodies targeting these epitopes are resistant to viral escape from neutralization and unde...

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Autores principales:	Thomas Krey, Annalisa Meola, Zhen-Yong Keck, Laurence Damier-Piolle, Steven K H Foung, Felix A Rey
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/7a34f878544d4b63971ddd2895bc189d
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spelling	oai:doaj.org-article:7a34f878544d4b63971ddd2895bc189d2021-11-18T06:05:38ZStructural basis of HCV neutralization by human monoclonal antibodies resistant to viral neutralization escape.1553-73661553-737410.1371/journal.ppat.1003364https://doaj.org/article/7a34f878544d4b63971ddd2895bc189d2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23696737/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374The high mutation rate of hepatitis C virus allows it to rapidly evade the humoral immune response. However, certain epitopes in the envelope glycoproteins cannot vary without compromising virus viability. Antibodies targeting these epitopes are resistant to viral escape from neutralization and understanding their binding-mode is important for vaccine design. Human monoclonal antibodies HC84-1 and HC84-27 target conformational epitopes overlapping the CD81 receptor-binding site, formed by segments aa434-446 and aa610-619 within the major HCV glycoprotein E2. No neutralization escape was yet observed for these antibodies. We report here the crystal structures of their Fab fragments in complex with a synthetic peptide comprising aa434-446. The structures show that the peptide adopts an α-helical conformation with the main contact residues F⁴⁴² and Y⁴⁴³ forming a hydrophobic protrusion. The peptide retained its conformation in both complexes, independently of crystal packing, indicating that it reflects a surface feature of the folded glycoprotein that is exposed similarly on the virion. The same residues of E2 are also involved in interaction with CD81, suggesting that the cellular receptor binds the same surface feature and potential escape mutants critically compromise receptor binding. In summary, our results identify a critical structural motif at the E2 surface, which is essential for virus propagation and therefore represents an ideal candidate for structure-based immunogen design for vaccine development.Thomas KreyAnnalisa MeolaZhen-Yong KeckLaurence Damier-PiolleSteven K H FoungFelix A ReyPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 5, p e1003364 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Thomas Krey Annalisa Meola Zhen-Yong Keck Laurence Damier-Piolle Steven K H Foung Felix A Rey Structural basis of HCV neutralization by human monoclonal antibodies resistant to viral neutralization escape.
description	The high mutation rate of hepatitis C virus allows it to rapidly evade the humoral immune response. However, certain epitopes in the envelope glycoproteins cannot vary without compromising virus viability. Antibodies targeting these epitopes are resistant to viral escape from neutralization and understanding their binding-mode is important for vaccine design. Human monoclonal antibodies HC84-1 and HC84-27 target conformational epitopes overlapping the CD81 receptor-binding site, formed by segments aa434-446 and aa610-619 within the major HCV glycoprotein E2. No neutralization escape was yet observed for these antibodies. We report here the crystal structures of their Fab fragments in complex with a synthetic peptide comprising aa434-446. The structures show that the peptide adopts an α-helical conformation with the main contact residues F⁴⁴² and Y⁴⁴³ forming a hydrophobic protrusion. The peptide retained its conformation in both complexes, independently of crystal packing, indicating that it reflects a surface feature of the folded glycoprotein that is exposed similarly on the virion. The same residues of E2 are also involved in interaction with CD81, suggesting that the cellular receptor binds the same surface feature and potential escape mutants critically compromise receptor binding. In summary, our results identify a critical structural motif at the E2 surface, which is essential for virus propagation and therefore represents an ideal candidate for structure-based immunogen design for vaccine development.
format	article
author	Thomas Krey Annalisa Meola Zhen-Yong Keck Laurence Damier-Piolle Steven K H Foung Felix A Rey
author_facet	Thomas Krey Annalisa Meola Zhen-Yong Keck Laurence Damier-Piolle Steven K H Foung Felix A Rey
author_sort	Thomas Krey
title	Structural basis of HCV neutralization by human monoclonal antibodies resistant to viral neutralization escape.
title_short	Structural basis of HCV neutralization by human monoclonal antibodies resistant to viral neutralization escape.
title_full	Structural basis of HCV neutralization by human monoclonal antibodies resistant to viral neutralization escape.
title_fullStr	Structural basis of HCV neutralization by human monoclonal antibodies resistant to viral neutralization escape.
title_full_unstemmed	Structural basis of HCV neutralization by human monoclonal antibodies resistant to viral neutralization escape.
title_sort	structural basis of hcv neutralization by human monoclonal antibodies resistant to viral neutralization escape.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/7a34f878544d4b63971ddd2895bc189d
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Structural basis of HCV neutralization by human monoclonal antibodies resistant to viral neutralization escape.

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