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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| Veröffentlicht in: | PLoS pathogens 2010-04, Vol.6 (4), p.e1000823-e1000823 |
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| creator | Shrestha, Bimmi Brien, James D Sukupolvi-Petty, Soila Austin, S Kyle Edeling, Melissa A Kim, Taekyung O'Brien, Katie M Nelson, Christopher A Johnson, Syd Fremont, Daved H Diamond, Michael S |
| 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. |
| doi_str_mv | 10.1371/journal.ppat.1000823 |
| format | Article |
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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.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1000823</identifier><identifier>PMID: 20369024</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amino Acid Sequence ; Animals ; Antibodies, Monoclonal ; Antibodies, Neutralizing - immunology ; Binding sites ; Causes of ; Cell culture ; Crystal structure ; Dengue ; Dengue fever ; Dengue Virus - genetics ; Dengue Virus - immunology ; Drug dosages ; Drug therapy ; Enzyme-Linked Immunosorbent Assay ; Epitope Mapping ; Epitopes, B-Lymphocyte - immunology ; Experiments ; Genetic aspects ; Genomes ; Genotype ; Genotype & phenotype ; Health aspects ; Humans ; Immunization ; Immunology/Immune Response ; Immunology/Immunity to Infections ; Infections ; Infectious Diseases/Viral Infections ; Mice ; Mice, Inbred C57BL ; Microbiology/Immunity to Infections ; Molecular Sequence Data ; Monoclonal antibodies ; Mortality ; Polymerase Chain Reaction ; Protein Structure, Tertiary ; Proteins ; Survival analysis ; Viral Envelope Proteins - chemistry ; Viral Envelope Proteins - genetics ; Viral Envelope Proteins - immunology ; West Nile fever</subject><ispartof>PLoS pathogens, 2010-04, Vol.6 (4), p.e1000823-e1000823</ispartof><rights>COPYRIGHT 2010 Public Library of Science</rights><rights>Shrestha et al. 2010</rights><rights>2010 Shrestha et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Shrestha B, Brien JD, Sukupolvi-Petty S, Austin SK, Edeling MA, et al. (2010) The Development of Therapeutic Antibodies That Neutralize Homologous and Heterologous Genotypes of Dengue Virus Type 1. 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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.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Antibodies, Monoclonal</subject><subject>Antibodies, Neutralizing - immunology</subject><subject>Binding sites</subject><subject>Causes of</subject><subject>Cell culture</subject><subject>Crystal structure</subject><subject>Dengue</subject><subject>Dengue fever</subject><subject>Dengue Virus - genetics</subject><subject>Dengue Virus - immunology</subject><subject>Drug dosages</subject><subject>Drug therapy</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Epitope Mapping</subject><subject>Epitopes, B-Lymphocyte - immunology</subject><subject>Experiments</subject><subject>Genetic aspects</subject><subject>Genomes</subject><subject>Genotype</subject><subject>Genotype & phenotype</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Immunization</subject><subject>Immunology/Immune Response</subject><subject>Immunology/Immunity to Infections</subject><subject>Infections</subject><subject>Infectious Diseases/Viral Infections</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Microbiology/Immunity to Infections</subject><subject>Molecular Sequence Data</subject><subject>Monoclonal antibodies</subject><subject>Mortality</subject><subject>Polymerase Chain Reaction</subject><subject>Protein Structure, Tertiary</subject><subject>Proteins</subject><subject>Survival analysis</subject><subject>Viral Envelope Proteins - chemistry</subject><subject>Viral Envelope Proteins - genetics</subject><subject>Viral Envelope Proteins - immunology</subject><subject>West Nile fever</subject><issn>1553-7374</issn><issn>1553-7366</issn><issn>1553-7374</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNqVkl2L1DAYhYso7rr6D0QLXogXM-azSW8WlsWPgUVB1-uQpm87GdqmJung-utNnc6yA95ICS0nzzkpJ2-WvcRojanA73du8oPu1uOo4xojhCShj7JzzDldCSrY4wffZ9mzEHYIMUxx8TQ7I4gWJSLsPNvfbiGvYQ-dG3sYYu6aPG7B6xGmaE2uh2grV1sISdYxH5LsdWd_Q751vetc66aQqDrfQgR_FFoYXLwbkyvl1TC0E-R769POrOb4efak0V2AF8v7Ivvx8cPt9efVzddPm-urm5UpKIkrLitGDSsZg7pGjOoGGNAkFYZSgKKq0iIVF2BwgRsJAjNUSWmw5MIITC-y14fcsXNBLZUFhYkskUgNlInYHIja6Z0ave21v1NOW_VXcL5V2qcmOlB1IxBryrIynLAKmrIqNdW8MoUWGuv5tMvltKnqoTapz9TVSejpzmC3qnV7RSSTnJMU8HYJ8O7nBCGq3gYDXacHSLUqQSljVJYz-eZAtjr9mR0alwLNTKsrQnhJheQoUet_UOmpobfGDdDYpJ8Y3p0YEhPhV2z1FILafP_2H-yXU5YdWONdCB6a-1IwUvM4H-9GzeOslnFOtlcPC703HeeX_gFCxfRk</recordid><startdate>20100401</startdate><enddate>20100401</enddate><creator>Shrestha, Bimmi</creator><creator>Brien, James D</creator><creator>Sukupolvi-Petty, Soila</creator><creator>Austin, S Kyle</creator><creator>Edeling, Melissa A</creator><creator>Kim, Taekyung</creator><creator>O'Brien, Katie M</creator><creator>Nelson, Christopher A</creator><creator>Johnson, Syd</creator><creator>Fremont, Daved H</creator><creator>Diamond, Michael S</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>ISN</scope><scope>ISR</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20100401</creationdate><title>The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1</title><author>Shrestha, Bimmi ; Brien, James D ; Sukupolvi-Petty, Soila ; Austin, S Kyle ; Edeling, Melissa A ; Kim, Taekyung ; O'Brien, Katie M ; Nelson, Christopher A ; Johnson, Syd ; Fremont, Daved H ; Diamond, Michael S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c632t-58b43c4944edd043afe4e343c6c33ee6bbe6b2b57ec161f8e7140b88c1857c713</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Antibodies, Monoclonal</topic><topic>Antibodies, Neutralizing - immunology</topic><topic>Binding sites</topic><topic>Causes of</topic><topic>Cell culture</topic><topic>Crystal structure</topic><topic>Dengue</topic><topic>Dengue fever</topic><topic>Dengue Virus - genetics</topic><topic>Dengue Virus - immunology</topic><topic>Drug dosages</topic><topic>Drug therapy</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Epitope Mapping</topic><topic>Epitopes, B-Lymphocyte - immunology</topic><topic>Experiments</topic><topic>Genetic aspects</topic><topic>Genomes</topic><topic>Genotype</topic><topic>Genotype & phenotype</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Immunization</topic><topic>Immunology/Immune Response</topic><topic>Immunology/Immunity to Infections</topic><topic>Infections</topic><topic>Infectious Diseases/Viral Infections</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Microbiology/Immunity to Infections</topic><topic>Molecular Sequence Data</topic><topic>Monoclonal antibodies</topic><topic>Mortality</topic><topic>Polymerase Chain Reaction</topic><topic>Protein Structure, Tertiary</topic><topic>Proteins</topic><topic>Survival analysis</topic><topic>Viral Envelope Proteins - chemistry</topic><topic>Viral Envelope Proteins - genetics</topic><topic>Viral Envelope Proteins - immunology</topic><topic>West Nile fever</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shrestha, Bimmi</creatorcontrib><creatorcontrib>Brien, James D</creatorcontrib><creatorcontrib>Sukupolvi-Petty, Soila</creatorcontrib><creatorcontrib>Austin, S Kyle</creatorcontrib><creatorcontrib>Edeling, Melissa A</creatorcontrib><creatorcontrib>Kim, Taekyung</creatorcontrib><creatorcontrib>O'Brien, Katie M</creatorcontrib><creatorcontrib>Nelson, Christopher A</creatorcontrib><creatorcontrib>Johnson, Syd</creatorcontrib><creatorcontrib>Fremont, Daved H</creatorcontrib><creatorcontrib>Diamond, Michael S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS pathogens</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shrestha, Bimmi</au><au>Brien, James D</au><au>Sukupolvi-Petty, Soila</au><au>Austin, S Kyle</au><au>Edeling, Melissa A</au><au>Kim, Taekyung</au><au>O'Brien, Katie M</au><au>Nelson, Christopher A</au><au>Johnson, Syd</au><au>Fremont, Daved H</au><au>Diamond, Michael S</au><au>Baric, Ralph S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1</atitle><jtitle>PLoS pathogens</jtitle><addtitle>PLoS Pathog</addtitle><date>2010-04-01</date><risdate>2010</risdate><volume>6</volume><issue>4</issue><spage>e1000823</spage><epage>e1000823</epage><pages>e1000823-e1000823</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><abstract>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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>20369024</pmid><doi>10.1371/journal.ppat.1000823</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Amino Acid Sequence Animals Antibodies, Monoclonal Antibodies, Neutralizing - immunology Binding sites Causes of Cell culture Crystal structure Dengue Dengue fever Dengue Virus - genetics Dengue Virus - immunology Drug dosages Drug therapy Enzyme-Linked Immunosorbent Assay Epitope Mapping Epitopes, B-Lymphocyte - immunology Experiments Genetic aspects Genomes Genotype Genotype & phenotype Health aspects Humans Immunization Immunology/Immune Response Immunology/Immunity to Infections Infections Infectious Diseases/Viral Infections Mice Mice, Inbred C57BL Microbiology/Immunity to Infections Molecular Sequence Data Monoclonal antibodies Mortality Polymerase Chain Reaction Protein Structure, Tertiary Proteins Survival analysis Viral Envelope Proteins - chemistry Viral Envelope Proteins - genetics Viral Envelope Proteins - immunology West Nile fever |
| title | The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1 |
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