The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1.

Antibody protection against flaviviruses is associated with the development of neutralizing antibodies against the viral envelope (E) protein. Prior studies with West Nile virus (WNV) identified therapeutic mouse and human monoclonal antibodies (MAbs) that recognized epitopes on domain III (DIII) of...

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Autores principales:	Bimmi Shrestha, James D Brien, Soila Sukupolvi-Petty, S Kyle Austin, Melissa A Edeling, Taekyung Kim, Katie M O'Brien, Christopher A Nelson, Syd Johnson, Daved H Fremont, Michael S Diamond
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/df704f99bc524bef9b9a3a5bc6a7a1a1
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spelling	oai:doaj.org-article:df704f99bc524bef9b9a3a5bc6a7a1a12021-11-25T05:48:10ZThe development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1.1553-73661553-737410.1371/journal.ppat.1000823https://doaj.org/article/df704f99bc524bef9b9a3a5bc6a7a1a12010-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20369024/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Antibody protection against flaviviruses is associated with the development of neutralizing antibodies against the viral envelope (E) protein. Prior studies with West Nile virus (WNV) identified therapeutic mouse and human monoclonal antibodies (MAbs) that recognized epitopes on domain III (DIII) of the E protein. To identify an analogous panel of neutralizing antibodies against DENV type-1 (DENV-1), we immunized mice with a genotype 2 strain of DENV-1 virus and generated 79 new MAbs, 16 of which strongly inhibited infection by the homologous virus and localized to DIII. Surprisingly, only two MAbs, DENV1-E105 and DENV1-E106, retained strong binding and neutralizing activity against all five DENV-1 genotypes. In an immunocompromised mouse model of infection, DENV1-E105 and DENV1-E106 exhibited therapeutic activity even when administered as a single dose four days after inoculation with a heterologous genotype 4 strain of DENV-1. Using epitope mapping and X-ray crystallographic analyses, we localized the neutralizing determinants for the strongly inhibitory MAbs to distinct regions on DIII. Interestingly, sequence variation in DIII alone failed to explain disparities in neutralizing potential of MAbs among different genotypes. Overall, our experiments define a complex structural epitope on DIII of DENV-1 that can be recognized by protective antibodies with therapeutic potential.Bimmi ShresthaJames D BrienSoila Sukupolvi-PettyS Kyle AustinMelissa A EdelingTaekyung KimKatie M O'BrienChristopher A NelsonSyd JohnsonDaved H FremontMichael S DiamondPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 6, Iss 4, p e1000823 (2010)
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 Bimmi Shrestha James D Brien Soila Sukupolvi-Petty S Kyle Austin Melissa A Edeling Taekyung Kim Katie M O'Brien Christopher A Nelson Syd Johnson Daved H Fremont Michael S Diamond The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1.
description	Antibody protection against flaviviruses is associated with the development of neutralizing antibodies against the viral envelope (E) protein. Prior studies with West Nile virus (WNV) identified therapeutic mouse and human monoclonal antibodies (MAbs) that recognized epitopes on domain III (DIII) of the E protein. To identify an analogous panel of neutralizing antibodies against DENV type-1 (DENV-1), we immunized mice with a genotype 2 strain of DENV-1 virus and generated 79 new MAbs, 16 of which strongly inhibited infection by the homologous virus and localized to DIII. Surprisingly, only two MAbs, DENV1-E105 and DENV1-E106, retained strong binding and neutralizing activity against all five DENV-1 genotypes. In an immunocompromised mouse model of infection, DENV1-E105 and DENV1-E106 exhibited therapeutic activity even when administered as a single dose four days after inoculation with a heterologous genotype 4 strain of DENV-1. Using epitope mapping and X-ray crystallographic analyses, we localized the neutralizing determinants for the strongly inhibitory MAbs to distinct regions on DIII. Interestingly, sequence variation in DIII alone failed to explain disparities in neutralizing potential of MAbs among different genotypes. Overall, our experiments define a complex structural epitope on DIII of DENV-1 that can be recognized by protective antibodies with therapeutic potential.
format	article
author	Bimmi Shrestha James D Brien Soila Sukupolvi-Petty S Kyle Austin Melissa A Edeling Taekyung Kim Katie M O'Brien Christopher A Nelson Syd Johnson Daved H Fremont Michael S Diamond
author_facet	Bimmi Shrestha James D Brien Soila Sukupolvi-Petty S Kyle Austin Melissa A Edeling Taekyung Kim Katie M O'Brien Christopher A Nelson Syd Johnson Daved H Fremont Michael S Diamond
author_sort	Bimmi Shrestha
title	The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1.
title_short	The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1.
title_full	The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1.
title_fullStr	The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1.
title_full_unstemmed	The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1.
title_sort	development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/df704f99bc524bef9b9a3a5bc6a7a1a1
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The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1.

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