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...

Full description

Bibliographic Details
Main Authors: 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
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2010-04-01
Series:PLoS Pathogens
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20369024/pdf/?tool=EBI
_version_ 1818930650900594688
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
collection DOAJ
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.
first_indexed 2024-12-20T04:04:05Z
format Article
id doaj.art-df704f99bc524bef9b9a3a5bc6a7a1a1
institution Directory Open Access Journal
issn 1553-7366
1553-7374
language English
last_indexed 2024-12-20T04:04:05Z
publishDate 2010-04-01
publisher Public Library of Science (PLoS)
record_format Article
series PLoS Pathogens
spelling doaj.art-df704f99bc524bef9b9a3a5bc6a7a1a12022-12-21T19:54:05ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742010-04-0164e100082310.1371/journal.ppat.1000823The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1.Bimmi ShresthaJames D BrienSoila Sukupolvi-PettyS Kyle AustinMelissa A EdelingTaekyung KimKatie M O'BrienChristopher A NelsonSyd JohnsonDaved H FremontMichael S DiamondAntibody 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20369024/pdf/?tool=EBI
spellingShingle 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.
PLoS Pathogens
title 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_short 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
url https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20369024/pdf/?tool=EBI
work_keys_str_mv AT bimmishrestha thedevelopmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT jamesdbrien thedevelopmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT soilasukupolvipetty thedevelopmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT skyleaustin thedevelopmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT melissaaedeling thedevelopmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT taekyungkim thedevelopmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT katiemobrien thedevelopmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT christopheranelson thedevelopmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT sydjohnson thedevelopmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT davedhfremont thedevelopmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT michaelsdiamond thedevelopmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT bimmishrestha developmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT jamesdbrien developmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT soilasukupolvipetty developmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT skyleaustin developmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT melissaaedeling developmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT taekyungkim developmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT katiemobrien developmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT christopheranelson developmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT sydjohnson developmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT davedhfremont developmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1
AT michaelsdiamond developmentoftherapeuticantibodiesthatneutralizehomologousandheterologousgenotypesofdenguevirustype1