Structural basis of differential neutralization of DENV-1 genotypes by an antibody that recognizes a cryptic epitope.

We previously developed a panel of neutralizing monoclonal antibodies against Dengue virus (DENV)-1, of which few exhibited inhibitory activity against all DENV-1 genotypes. This finding is consistent with reports observing variable neutralization of different DENV strains and genotypes using serum...

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Autores principales:	S Kyle Austin, Kimberly A Dowd, Bimmi Shrestha, Christopher A Nelson, Melissa A Edeling, Syd Johnson, Theodore C Pierson, Michael S Diamond, Daved H Fremont
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1b208d14ff4c44678b1d5ccad2b34bc2
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spelling	oai:doaj.org-article:1b208d14ff4c44678b1d5ccad2b34bc22021-11-18T06:06:30ZStructural basis of differential neutralization of DENV-1 genotypes by an antibody that recognizes a cryptic epitope.1553-73661553-737410.1371/journal.ppat.1002930https://doaj.org/article/1b208d14ff4c44678b1d5ccad2b34bc22012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23055922/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374We previously developed a panel of neutralizing monoclonal antibodies against Dengue virus (DENV)-1, of which few exhibited inhibitory activity against all DENV-1 genotypes. This finding is consistent with reports observing variable neutralization of different DENV strains and genotypes using serum from individuals that experienced natural infection or immunization. Herein, we describe the crystal structures of DENV1-E111 bound to a novel CC' loop epitope on domain III (DIII) of the E protein from two different DENV-1 genotypes. Docking of our structure onto the available cryo-electron microscopy models of DENV virions revealed that the DENV1-E111 epitope was inaccessible, suggesting that this antibody recognizes an uncharacterized virus conformation. While the affinity of binding between DENV1-E111 and DIII varied by genotype, we observed limited correlation with inhibitory activity. Instead, our results support the conclusion that potent neutralization depends on genotype-dependent exposure of the CC' loop epitope. These findings establish new structural complexity of the DENV virion, which may be relevant for the choice of DENV strain for induction or analysis of neutralizing antibodies in the context of vaccine development.S Kyle AustinKimberly A DowdBimmi ShresthaChristopher A NelsonMelissa A EdelingSyd JohnsonTheodore C PiersonMichael S DiamondDaved H FremontPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 8, Iss 10, p e1002930 (2012)
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 S Kyle Austin Kimberly A Dowd Bimmi Shrestha Christopher A Nelson Melissa A Edeling Syd Johnson Theodore C Pierson Michael S Diamond Daved H Fremont Structural basis of differential neutralization of DENV-1 genotypes by an antibody that recognizes a cryptic epitope.
description	We previously developed a panel of neutralizing monoclonal antibodies against Dengue virus (DENV)-1, of which few exhibited inhibitory activity against all DENV-1 genotypes. This finding is consistent with reports observing variable neutralization of different DENV strains and genotypes using serum from individuals that experienced natural infection or immunization. Herein, we describe the crystal structures of DENV1-E111 bound to a novel CC' loop epitope on domain III (DIII) of the E protein from two different DENV-1 genotypes. Docking of our structure onto the available cryo-electron microscopy models of DENV virions revealed that the DENV1-E111 epitope was inaccessible, suggesting that this antibody recognizes an uncharacterized virus conformation. While the affinity of binding between DENV1-E111 and DIII varied by genotype, we observed limited correlation with inhibitory activity. Instead, our results support the conclusion that potent neutralization depends on genotype-dependent exposure of the CC' loop epitope. These findings establish new structural complexity of the DENV virion, which may be relevant for the choice of DENV strain for induction or analysis of neutralizing antibodies in the context of vaccine development.
format	article
author	S Kyle Austin Kimberly A Dowd Bimmi Shrestha Christopher A Nelson Melissa A Edeling Syd Johnson Theodore C Pierson Michael S Diamond Daved H Fremont
author_facet	S Kyle Austin Kimberly A Dowd Bimmi Shrestha Christopher A Nelson Melissa A Edeling Syd Johnson Theodore C Pierson Michael S Diamond Daved H Fremont
author_sort	S Kyle Austin
title	Structural basis of differential neutralization of DENV-1 genotypes by an antibody that recognizes a cryptic epitope.
title_short	Structural basis of differential neutralization of DENV-1 genotypes by an antibody that recognizes a cryptic epitope.
title_full	Structural basis of differential neutralization of DENV-1 genotypes by an antibody that recognizes a cryptic epitope.
title_fullStr	Structural basis of differential neutralization of DENV-1 genotypes by an antibody that recognizes a cryptic epitope.
title_full_unstemmed	Structural basis of differential neutralization of DENV-1 genotypes by an antibody that recognizes a cryptic epitope.
title_sort	structural basis of differential neutralization of denv-1 genotypes by an antibody that recognizes a cryptic epitope.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/1b208d14ff4c44678b1d5ccad2b34bc2
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Structural basis of differential neutralization of DENV-1 genotypes by an antibody that recognizes a cryptic epitope.

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