Genotypic Differences in Dengue Virus Neutralization Are Explained by a Single Amino Acid Mutation That Modulates Virus Breathing

ABSTRACT Flaviviruses sample an ensemble of virion conformations resulting from the conformational flexibility of their structural proteins. To investigate how sequence variation among strains impacts virus breathing, we performed studies with the monoclonal antibody (MAb) E111, which binds an inacc...

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Autores principales:	Kimberly A. Dowd, Christina R. DeMaso, Theodore C. Pierson
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a8d04135145e4f91b260faa27f5d3516
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spelling	oai:doaj.org-article:a8d04135145e4f91b260faa27f5d35162021-11-15T15:41:22ZGenotypic Differences in Dengue Virus Neutralization Are Explained by a Single Amino Acid Mutation That Modulates Virus Breathing10.1128/mBio.01559-152150-7511https://doaj.org/article/a8d04135145e4f91b260faa27f5d35162015-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01559-15https://doaj.org/toc/2150-7511ABSTRACT Flaviviruses sample an ensemble of virion conformations resulting from the conformational flexibility of their structural proteins. To investigate how sequence variation among strains impacts virus breathing, we performed studies with the monoclonal antibody (MAb) E111, which binds an inaccessible domain III envelope (E) protein epitope of dengue virus serotype 1 (DENV1). Prior studies indicated that an observed ~200-fold difference in neutralization between the DENV1 strains Western Pacific-74 (West Pac-74) and 16007 could not be explained by differences in the affinity of MAb E111 for each strain. Through neutralization studies with wild-type and variant viruses carrying genes encoding reciprocal mutations at all 13 amino acid differences between the E proteins of West Pac-74 and 16007, we found that E111 neutralization susceptibility mapped solely to the presence of a lysine or arginine at E domain II residue 204, located distally from the E111 epitope. This same residue correlated with neutralization differences observed for MAbs specific for epitopes distinct from E111, suggesting that this amino acid dictates changes in the conformational ensembles sampled by the virus. Furthermore, an observed twofold difference in the stability of infectious West Pac-74 versus 16007 in solution also mapped to E residue 204. Our results demonstrate that neutralization susceptibility can be altered in an epitope-independent manner by natural strain variation that influences the structures sampled by DENV. That different conformational ensembles of flaviviruses may affect the landscape available for antibody binding, as well as virus stability, has important implications for functional studies of antibody potency, a critical aspect of vaccine development. IMPORTANCE The global burden of dengue virus (DENV) is growing, with recent estimates of ~390 million human infections each year. Antibodies play a crucial role in protection from DENV infection, and vaccines that elicit a robust antibody response are being actively pursued. We report here the identification of a single amino acid residue in the envelope protein of DENV serotype 1 that results in global changes to virus structure and stability when it is changed. Our results indicate that naturally occurring variation at this particular site among virus strains impacts the ensemble of structures sampled by the virus, a process referred to as virus breathing. The finding that such limited and conservative sequence changes can modulate the landscape available for antibody binding has important implications for both vaccine development and the study of DENV-reactive antibodies.Kimberly A. DowdChristina R. DeMasoTheodore C. PiersonAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 6 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Kimberly A. Dowd Christina R. DeMaso Theodore C. Pierson Genotypic Differences in Dengue Virus Neutralization Are Explained by a Single Amino Acid Mutation That Modulates Virus Breathing
description	ABSTRACT Flaviviruses sample an ensemble of virion conformations resulting from the conformational flexibility of their structural proteins. To investigate how sequence variation among strains impacts virus breathing, we performed studies with the monoclonal antibody (MAb) E111, which binds an inaccessible domain III envelope (E) protein epitope of dengue virus serotype 1 (DENV1). Prior studies indicated that an observed ~200-fold difference in neutralization between the DENV1 strains Western Pacific-74 (West Pac-74) and 16007 could not be explained by differences in the affinity of MAb E111 for each strain. Through neutralization studies with wild-type and variant viruses carrying genes encoding reciprocal mutations at all 13 amino acid differences between the E proteins of West Pac-74 and 16007, we found that E111 neutralization susceptibility mapped solely to the presence of a lysine or arginine at E domain II residue 204, located distally from the E111 epitope. This same residue correlated with neutralization differences observed for MAbs specific for epitopes distinct from E111, suggesting that this amino acid dictates changes in the conformational ensembles sampled by the virus. Furthermore, an observed twofold difference in the stability of infectious West Pac-74 versus 16007 in solution also mapped to E residue 204. Our results demonstrate that neutralization susceptibility can be altered in an epitope-independent manner by natural strain variation that influences the structures sampled by DENV. That different conformational ensembles of flaviviruses may affect the landscape available for antibody binding, as well as virus stability, has important implications for functional studies of antibody potency, a critical aspect of vaccine development. IMPORTANCE The global burden of dengue virus (DENV) is growing, with recent estimates of ~390 million human infections each year. Antibodies play a crucial role in protection from DENV infection, and vaccines that elicit a robust antibody response are being actively pursued. We report here the identification of a single amino acid residue in the envelope protein of DENV serotype 1 that results in global changes to virus structure and stability when it is changed. Our results indicate that naturally occurring variation at this particular site among virus strains impacts the ensemble of structures sampled by the virus, a process referred to as virus breathing. The finding that such limited and conservative sequence changes can modulate the landscape available for antibody binding has important implications for both vaccine development and the study of DENV-reactive antibodies.
format	article
author	Kimberly A. Dowd Christina R. DeMaso Theodore C. Pierson
author_facet	Kimberly A. Dowd Christina R. DeMaso Theodore C. Pierson
author_sort	Kimberly A. Dowd
title	Genotypic Differences in Dengue Virus Neutralization Are Explained by a Single Amino Acid Mutation That Modulates Virus Breathing
title_short	Genotypic Differences in Dengue Virus Neutralization Are Explained by a Single Amino Acid Mutation That Modulates Virus Breathing
title_full	Genotypic Differences in Dengue Virus Neutralization Are Explained by a Single Amino Acid Mutation That Modulates Virus Breathing
title_fullStr	Genotypic Differences in Dengue Virus Neutralization Are Explained by a Single Amino Acid Mutation That Modulates Virus Breathing
title_full_unstemmed	Genotypic Differences in Dengue Virus Neutralization Are Explained by a Single Amino Acid Mutation That Modulates Virus Breathing
title_sort	genotypic differences in dengue virus neutralization are explained by a single amino acid mutation that modulates virus breathing
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/a8d04135145e4f91b260faa27f5d3516
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Genotypic Differences in Dengue Virus Neutralization Are Explained by a Single Amino Acid Mutation That Modulates Virus Breathing

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