Immunogenetic Mechanisms Driving Norovirus GII.4 Antigenic Variation

Noroviruses are the principal cause of epidemic gastroenteritis worldwide with GII.4 strains accounting for 80% of infections. The major capsid protein of GII.4 strains is evolving rapidly, resulting in new epidemic strains with altered antigenic potentials. To test if antigenic drift may contribute...

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Main Authors:	Lindesmith, Lisa C., Beltramello, Martina, Donaldson, Eric F., Corti, Davide, Swanstrom, Jesica, Debbink, Kari, Lanzavecchia, Antonio, Baric, Ralph S.
Format:	Online
Language:	English
Published:	Public Library of Science 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355092/

id	pubmed-3355092
recordtype	oai_dc
spelling	pubmed-33550922012-05-21 Immunogenetic Mechanisms Driving Norovirus GII.4 Antigenic Variation Lindesmith, Lisa C. Beltramello, Martina Donaldson, Eric F. Corti, Davide Swanstrom, Jesica Debbink, Kari Lanzavecchia, Antonio Baric, Ralph S. Research Article Noroviruses are the principal cause of epidemic gastroenteritis worldwide with GII.4 strains accounting for 80% of infections. The major capsid protein of GII.4 strains is evolving rapidly, resulting in new epidemic strains with altered antigenic potentials. To test if antigenic drift may contribute to GII.4 persistence, human memory B cells were immortalized and the resulting human monoclonal antibodies (mAbs) characterized for reactivity to a panel of time-ordered GII.4 virus-like particles (VLPs). Reflecting the complex exposure history of the volunteer, human anti-GII.4 mAbs grouped into three VLP reactivity patterns; ancestral (1987–1997), contemporary (2004–2009), and broad (1987–2009). NVB 114 reacted exclusively to the earliest GII.4 VLPs by EIA and blockade. NVB 97 specifically bound and blocked only contemporary GII.4 VLPs, while NBV 111 and 43.9 exclusively reacted with and blocked variants of the GII.4.2006 Minerva strain. Three mAbs had broad GII.4 reactivity. Two, NVB 37.10 and 61.3, also detected other genogroup II VLPs by EIA but did not block any VLP interactions with carbohydrate ligands. NVB 71.4 cross-neutralized the panel of time-ordered GII.4 VLPs, as measured by VLP-carbohydrate blockade assays. Using mutant VLPs designed to alter predicted antigenic epitopes, two evolving, GII.4-specific, blockade epitopes were mapped. Amino acids 294–298 and 368–372 were required for binding NVB 114, 111 and 43.9 mAbs. Amino acids 393–395 were essential for binding NVB 97, supporting earlier correlations between antibody blockade escape and carbohydrate binding variation. These data inform VLP vaccine design, provide a strategy for expanding the cross-blockade potential of chimeric VLP vaccines, and identify an antibody with broadly neutralizing therapeutic potential for the treatment of human disease. Moreover, these data support the hypothesis that GII.4 norovirus evolution is heavily influenced by antigenic variation of neutralizing epitopes and consequently, antibody-driven receptor switching; thus, protective herd immunity is a driving force in norovirus molecular evolution. Public Library of Science 2012-05-17 /pmc/articles/PMC3355092/ /pubmed/22615565 http://dx.doi.org/10.1371/journal.ppat.1002705 Text en Lindesmith et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Lindesmith, Lisa C. Beltramello, Martina Donaldson, Eric F. Corti, Davide Swanstrom, Jesica Debbink, Kari Lanzavecchia, Antonio Baric, Ralph S.
spellingShingle	Lindesmith, Lisa C. Beltramello, Martina Donaldson, Eric F. Corti, Davide Swanstrom, Jesica Debbink, Kari Lanzavecchia, Antonio Baric, Ralph S. Immunogenetic Mechanisms Driving Norovirus GII.4 Antigenic Variation
author_facet	Lindesmith, Lisa C. Beltramello, Martina Donaldson, Eric F. Corti, Davide Swanstrom, Jesica Debbink, Kari Lanzavecchia, Antonio Baric, Ralph S.
author_sort	Lindesmith, Lisa C.
title	Immunogenetic Mechanisms Driving Norovirus GII.4 Antigenic Variation
title_short	Immunogenetic Mechanisms Driving Norovirus GII.4 Antigenic Variation
title_full	Immunogenetic Mechanisms Driving Norovirus GII.4 Antigenic Variation
title_fullStr	Immunogenetic Mechanisms Driving Norovirus GII.4 Antigenic Variation
title_full_unstemmed	Immunogenetic Mechanisms Driving Norovirus GII.4 Antigenic Variation
title_sort	immunogenetic mechanisms driving norovirus gii.4 antigenic variation
description	Noroviruses are the principal cause of epidemic gastroenteritis worldwide with GII.4 strains accounting for 80% of infections. The major capsid protein of GII.4 strains is evolving rapidly, resulting in new epidemic strains with altered antigenic potentials. To test if antigenic drift may contribute to GII.4 persistence, human memory B cells were immortalized and the resulting human monoclonal antibodies (mAbs) characterized for reactivity to a panel of time-ordered GII.4 virus-like particles (VLPs). Reflecting the complex exposure history of the volunteer, human anti-GII.4 mAbs grouped into three VLP reactivity patterns; ancestral (1987–1997), contemporary (2004–2009), and broad (1987–2009). NVB 114 reacted exclusively to the earliest GII.4 VLPs by EIA and blockade. NVB 97 specifically bound and blocked only contemporary GII.4 VLPs, while NBV 111 and 43.9 exclusively reacted with and blocked variants of the GII.4.2006 Minerva strain. Three mAbs had broad GII.4 reactivity. Two, NVB 37.10 and 61.3, also detected other genogroup II VLPs by EIA but did not block any VLP interactions with carbohydrate ligands. NVB 71.4 cross-neutralized the panel of time-ordered GII.4 VLPs, as measured by VLP-carbohydrate blockade assays. Using mutant VLPs designed to alter predicted antigenic epitopes, two evolving, GII.4-specific, blockade epitopes were mapped. Amino acids 294–298 and 368–372 were required for binding NVB 114, 111 and 43.9 mAbs. Amino acids 393–395 were essential for binding NVB 97, supporting earlier correlations between antibody blockade escape and carbohydrate binding variation. These data inform VLP vaccine design, provide a strategy for expanding the cross-blockade potential of chimeric VLP vaccines, and identify an antibody with broadly neutralizing therapeutic potential for the treatment of human disease. Moreover, these data support the hypothesis that GII.4 norovirus evolution is heavily influenced by antigenic variation of neutralizing epitopes and consequently, antibody-driven receptor switching; thus, protective herd immunity is a driving force in norovirus molecular evolution.
publisher	Public Library of Science
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355092/
_version_	1611530775713284096

Immunogenetic Mechanisms Driving Norovirus GII.4 Antigenic Variation

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