Characterization of a Prefusion-Specific Antibody That Recognizes a Quaternary, Cleavage-Dependent Epitope on the RSV Fusion Glycoprotein.
Prevention efforts for respiratory syncytial virus (RSV) have been advanced due to the recent isolation and characterization of antibodies that specifically recognize the prefusion conformation of the RSV fusion (F) glycoprotein. These potently neutralizing antibodies are in clinical development for...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-07-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1005035 |
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| author | Morgan S A Gilman Syed M Moin Vicente Mas Man Chen Nita K Patel Kari Kramer Qing Zhu Stephanie C Kabeche Azad Kumar Concepción Palomo Tim Beaumont Ulrich Baxa Nancy D Ulbrandt José A Melero Barney S Graham Jason S McLellan |
| author_facet | Morgan S A Gilman Syed M Moin Vicente Mas Man Chen Nita K Patel Kari Kramer Qing Zhu Stephanie C Kabeche Azad Kumar Concepción Palomo Tim Beaumont Ulrich Baxa Nancy D Ulbrandt José A Melero Barney S Graham Jason S McLellan |
| author_sort | Morgan S A Gilman |
| collection | DOAJ |
| description | Prevention efforts for respiratory syncytial virus (RSV) have been advanced due to the recent isolation and characterization of antibodies that specifically recognize the prefusion conformation of the RSV fusion (F) glycoprotein. These potently neutralizing antibodies are in clinical development for passive prophylaxis and have also aided the design of vaccine antigens that display prefusion-specific epitopes. To date, prefusion-specific antibodies have been shown to target two antigenic sites on RSV F, but both of these sites are also present on monomeric forms of F. Here we present a structural and functional characterization of human antibody AM14, which potently neutralized laboratory strains and clinical isolates of RSV from both A and B subtypes. The crystal structure and location of escape mutations revealed that AM14 recognizes a quaternary epitope that spans two protomers and includes a region that undergoes extensive conformational changes in the pre- to postfusion F transition. Binding assays demonstrated that AM14 is unique in its specific recognition of trimeric furin-cleaved prefusion F, which is the mature form of F on infectious virions. These results demonstrate that the prefusion F trimer contains potent neutralizing epitopes not present on monomers and that AM14 should be particularly useful for characterizing the conformational state of RSV F-based vaccine antigens. |
| format | Article |
| id | doaj-art-6bbdfb9a96f440d5a4a0d09486df35de |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2015-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-6bbdfb9a96f440d5a4a0d09486df35de2025-08-20T03:46:13ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742015-07-01117e100503510.1371/journal.ppat.1005035Characterization of a Prefusion-Specific Antibody That Recognizes a Quaternary, Cleavage-Dependent Epitope on the RSV Fusion Glycoprotein.Morgan S A GilmanSyed M MoinVicente MasMan ChenNita K PatelKari KramerQing ZhuStephanie C KabecheAzad KumarConcepción PalomoTim BeaumontUlrich BaxaNancy D UlbrandtJosé A MeleroBarney S GrahamJason S McLellanPrevention efforts for respiratory syncytial virus (RSV) have been advanced due to the recent isolation and characterization of antibodies that specifically recognize the prefusion conformation of the RSV fusion (F) glycoprotein. These potently neutralizing antibodies are in clinical development for passive prophylaxis and have also aided the design of vaccine antigens that display prefusion-specific epitopes. To date, prefusion-specific antibodies have been shown to target two antigenic sites on RSV F, but both of these sites are also present on monomeric forms of F. Here we present a structural and functional characterization of human antibody AM14, which potently neutralized laboratory strains and clinical isolates of RSV from both A and B subtypes. The crystal structure and location of escape mutations revealed that AM14 recognizes a quaternary epitope that spans two protomers and includes a region that undergoes extensive conformational changes in the pre- to postfusion F transition. Binding assays demonstrated that AM14 is unique in its specific recognition of trimeric furin-cleaved prefusion F, which is the mature form of F on infectious virions. These results demonstrate that the prefusion F trimer contains potent neutralizing epitopes not present on monomers and that AM14 should be particularly useful for characterizing the conformational state of RSV F-based vaccine antigens.https://doi.org/10.1371/journal.ppat.1005035 |
| spellingShingle | Morgan S A Gilman Syed M Moin Vicente Mas Man Chen Nita K Patel Kari Kramer Qing Zhu Stephanie C Kabeche Azad Kumar Concepción Palomo Tim Beaumont Ulrich Baxa Nancy D Ulbrandt José A Melero Barney S Graham Jason S McLellan Characterization of a Prefusion-Specific Antibody That Recognizes a Quaternary, Cleavage-Dependent Epitope on the RSV Fusion Glycoprotein. PLoS Pathogens |
| title | Characterization of a Prefusion-Specific Antibody That Recognizes a Quaternary, Cleavage-Dependent Epitope on the RSV Fusion Glycoprotein. |
| title_full | Characterization of a Prefusion-Specific Antibody That Recognizes a Quaternary, Cleavage-Dependent Epitope on the RSV Fusion Glycoprotein. |
| title_fullStr | Characterization of a Prefusion-Specific Antibody That Recognizes a Quaternary, Cleavage-Dependent Epitope on the RSV Fusion Glycoprotein. |
| title_full_unstemmed | Characterization of a Prefusion-Specific Antibody That Recognizes a Quaternary, Cleavage-Dependent Epitope on the RSV Fusion Glycoprotein. |
| title_short | Characterization of a Prefusion-Specific Antibody That Recognizes a Quaternary, Cleavage-Dependent Epitope on the RSV Fusion Glycoprotein. |
| title_sort | characterization of a prefusion specific antibody that recognizes a quaternary cleavage dependent epitope on the rsv fusion glycoprotein |
| url | https://doi.org/10.1371/journal.ppat.1005035 |
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