Conformational Occlusion of Blockade Antibody Epitopes, a Novel Mechanism of GII.4 Human Norovirus Immune Evasion

ABSTRACT Extensive antigenic diversity within the GII.4 genotype of human norovirus is a major driver of pandemic emergence and a significant obstacle to development of cross-protective immunity after natural infection and vaccination. However, human and mouse monoclonal antibody studies indicate th...

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Autores principales:	Lisa C. Lindesmith, Michael L. Mallory, Kari Debbink, Eric F. Donaldson, Paul D. Brewer-Jensen, Excel W. Swann, Timothy P. Sheahan, Rachel L. Graham, Martina Beltramello, Davide Corti, Antonio Lanzavecchia, Ralph S. Baric
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	adaptive immunity blockade antibody broadly neutralizing antibody epitope shielding evolution immune evasion Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3234b0dad85f46aab63b050645be5abc
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spelling	oai:doaj.org-article:3234b0dad85f46aab63b050645be5abc2021-11-15T15:22:02ZConformational Occlusion of Blockade Antibody Epitopes, a Novel Mechanism of GII.4 Human Norovirus Immune Evasion10.1128/mSphere.00518-172379-5042https://doaj.org/article/3234b0dad85f46aab63b050645be5abc2018-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00518-17https://doaj.org/toc/2379-5042ABSTRACT Extensive antigenic diversity within the GII.4 genotype of human norovirus is a major driver of pandemic emergence and a significant obstacle to development of cross-protective immunity after natural infection and vaccination. However, human and mouse monoclonal antibody studies indicate that, although rare, antibodies to conserved GII.4 blockade epitopes are generated. The mechanisms by which these epitopes evade immune surveillance are uncertain. Here, we developed a new approach for identifying conserved GII.4 norovirus epitopes. Utilizing a unique set of virus-like particles (VLPs) representing the in vivo-evolved sequence diversity within an immunocompromised person, we identify key residues within epitope F, a conserved GII.4 blockade antibody epitope. The residues critical for antibody binding are proximal to evolving blockade epitope E. Like epitope F, antibody blockade of epitope E was temperature sensitive, indicating that particle conformation regulates antibody access not only to the conserved GII.4 blockade epitope F but also to the evolving epitope E. These data highlight novel GII.4 mechanisms to protect blockade antibody epitopes, map essential residues of a GII.4 conserved epitope, and expand our understanding of how viral particle dynamics may drive antigenicity and antibody-mediated protection by effectively shielding blockade epitopes. Our data support the notion that GII.4 particle breathing may well represent a major mechanism of humoral immune evasion supporting cyclic pandemic virus persistence and spread in human populations. IMPORTANCE In this study, we use norovirus virus-like particles to identify key residues of a conserved GII.4 blockade antibody epitope. Further, we identify an additional GII.4 blockade antibody epitope to be occluded, with antibody access governed by temperature and particle dynamics. These findings provide additional support for particle conformation-based presentation of binding residues mediated by a particle “breathing core.” Together, these data suggest that limiting antibody access to blockade antibody epitopes may be a frequent mechanism of immune evasion for GII.4 human noroviruses. Mapping blockade antibody epitopes, the interaction between adjacent epitopes on the particle, and the breathing core that mediates antibody access to epitopes provides greater mechanistic understanding of epitope camouflage strategies utilized by human viral pathogens to evade immunity.Lisa C. LindesmithMichael L. MalloryKari DebbinkEric F. DonaldsonPaul D. Brewer-JensenExcel W. SwannTimothy P. SheahanRachel L. GrahamMartina BeltramelloDavide CortiAntonio LanzavecchiaRalph S. BaricAmerican Society for Microbiologyarticleadaptive immunityblockade antibodybroadly neutralizing antibodyepitope shieldingevolutionimmune evasionMicrobiologyQR1-502ENmSphere, Vol 3, Iss 1 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	adaptive immunity blockade antibody broadly neutralizing antibody epitope shielding evolution immune evasion Microbiology QR1-502
spellingShingle	adaptive immunity blockade antibody broadly neutralizing antibody epitope shielding evolution immune evasion Microbiology QR1-502 Lisa C. Lindesmith Michael L. Mallory Kari Debbink Eric F. Donaldson Paul D. Brewer-Jensen Excel W. Swann Timothy P. Sheahan Rachel L. Graham Martina Beltramello Davide Corti Antonio Lanzavecchia Ralph S. Baric Conformational Occlusion of Blockade Antibody Epitopes, a Novel Mechanism of GII.4 Human Norovirus Immune Evasion
description	ABSTRACT Extensive antigenic diversity within the GII.4 genotype of human norovirus is a major driver of pandemic emergence and a significant obstacle to development of cross-protective immunity after natural infection and vaccination. However, human and mouse monoclonal antibody studies indicate that, although rare, antibodies to conserved GII.4 blockade epitopes are generated. The mechanisms by which these epitopes evade immune surveillance are uncertain. Here, we developed a new approach for identifying conserved GII.4 norovirus epitopes. Utilizing a unique set of virus-like particles (VLPs) representing the in vivo-evolved sequence diversity within an immunocompromised person, we identify key residues within epitope F, a conserved GII.4 blockade antibody epitope. The residues critical for antibody binding are proximal to evolving blockade epitope E. Like epitope F, antibody blockade of epitope E was temperature sensitive, indicating that particle conformation regulates antibody access not only to the conserved GII.4 blockade epitope F but also to the evolving epitope E. These data highlight novel GII.4 mechanisms to protect blockade antibody epitopes, map essential residues of a GII.4 conserved epitope, and expand our understanding of how viral particle dynamics may drive antigenicity and antibody-mediated protection by effectively shielding blockade epitopes. Our data support the notion that GII.4 particle breathing may well represent a major mechanism of humoral immune evasion supporting cyclic pandemic virus persistence and spread in human populations. IMPORTANCE In this study, we use norovirus virus-like particles to identify key residues of a conserved GII.4 blockade antibody epitope. Further, we identify an additional GII.4 blockade antibody epitope to be occluded, with antibody access governed by temperature and particle dynamics. These findings provide additional support for particle conformation-based presentation of binding residues mediated by a particle “breathing core.” Together, these data suggest that limiting antibody access to blockade antibody epitopes may be a frequent mechanism of immune evasion for GII.4 human noroviruses. Mapping blockade antibody epitopes, the interaction between adjacent epitopes on the particle, and the breathing core that mediates antibody access to epitopes provides greater mechanistic understanding of epitope camouflage strategies utilized by human viral pathogens to evade immunity.
format	article
author	Lisa C. Lindesmith Michael L. Mallory Kari Debbink Eric F. Donaldson Paul D. Brewer-Jensen Excel W. Swann Timothy P. Sheahan Rachel L. Graham Martina Beltramello Davide Corti Antonio Lanzavecchia Ralph S. Baric
author_facet	Lisa C. Lindesmith Michael L. Mallory Kari Debbink Eric F. Donaldson Paul D. Brewer-Jensen Excel W. Swann Timothy P. Sheahan Rachel L. Graham Martina Beltramello Davide Corti Antonio Lanzavecchia Ralph S. Baric
author_sort	Lisa C. Lindesmith
title	Conformational Occlusion of Blockade Antibody Epitopes, a Novel Mechanism of GII.4 Human Norovirus Immune Evasion
title_short	Conformational Occlusion of Blockade Antibody Epitopes, a Novel Mechanism of GII.4 Human Norovirus Immune Evasion
title_full	Conformational Occlusion of Blockade Antibody Epitopes, a Novel Mechanism of GII.4 Human Norovirus Immune Evasion
title_fullStr	Conformational Occlusion of Blockade Antibody Epitopes, a Novel Mechanism of GII.4 Human Norovirus Immune Evasion
title_full_unstemmed	Conformational Occlusion of Blockade Antibody Epitopes, a Novel Mechanism of GII.4 Human Norovirus Immune Evasion
title_sort	conformational occlusion of blockade antibody epitopes, a novel mechanism of gii.4 human norovirus immune evasion
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/3234b0dad85f46aab63b050645be5abc
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Conformational Occlusion of Blockade Antibody Epitopes, a Novel Mechanism of GII.4 Human Norovirus Immune Evasion

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