A single amino acid mutation alters multiple neutralization epitopes in the respiratory syncytial virus fusion glycoprotein
Abstract Respiratory syncytial virus (RSV) is the leading cause of infant hospitalization. All current RSV therapeutics, including antibody prophylaxis and adult vaccination, target the RSV fusion glycoprotein (RSV-F). The seven neutralization sites on RSV-F are highly conserved and infrequently mut...
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Nature Portfolio
2025-04-01
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| Series: | npj Viruses |
| Online Access: | https://doi.org/10.1038/s44298-025-00119-8 |
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| author | Ahmed K. Oraby Aleksandra Stojic Farah Elawar Leanne M. Bilawchuk Ryley D. McClelland Kaci Erwin Madison J. Granoski Cameron D. Griffiths Justin D. Frederick Elena Arutyunova M. Joanne Lemieux Frederick. G. West Octavio Ramilo Asuncion Mejias Jason S. McLellan David J. Marchant |
| author_facet | Ahmed K. Oraby Aleksandra Stojic Farah Elawar Leanne M. Bilawchuk Ryley D. McClelland Kaci Erwin Madison J. Granoski Cameron D. Griffiths Justin D. Frederick Elena Arutyunova M. Joanne Lemieux Frederick. G. West Octavio Ramilo Asuncion Mejias Jason S. McLellan David J. Marchant |
| author_sort | Ahmed K. Oraby |
| collection | DOAJ |
| description | Abstract Respiratory syncytial virus (RSV) is the leading cause of infant hospitalization. All current RSV therapeutics, including antibody prophylaxis and adult vaccination, target the RSV fusion glycoprotein (RSV-F). The seven neutralization sites on RSV-F are highly conserved and infrequently mutate. Here, we show that a single amino acid mutation at position 305 in RSV-F significantly alters antigenic recognition of RSV-F binding sites and reduces the susceptibility of RSV to neutralizing antibodies. In an in vitro evolution assay, we show that RSV-F L305I occurs in a majority of RSV quasi-species. Computational modeling predicted that the L305I mutation altered the epitope landscape of RSV-F, resulting in changes to neutralizing antibody sensitivity and affinity towards the RSV-F glycoprotein. Screening of published RSV-F sequences revealed that position 305 in RSV-F was conserved with a leucine and isoleucine in RSV-A and RSV-B subtypes respectively. Our study suggests that select amino acids in RSV-F may act as ‘conformational switches’ for RSV to evade host serum antibodies. This work has important implications in understanding RSV evolution and resistance as it suggests that mutational resistance to neutralizing antibodies can occur at sites distal to antigenic epitopes, significantly altering antibody sensitivity to viral infection. These unique antigenic landscape changes should be considered in the context of vaccine and therapeutic development in order to better understand viral mechanisms of evasion and resistance. |
| format | Article |
| id | doaj-art-25e310fbede84408bf88c73f8ef61780 |
| institution | DOAJ |
| issn | 2948-1767 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Viruses |
| spelling | doaj-art-25e310fbede84408bf88c73f8ef617802025-08-20T03:14:07ZengNature Portfolionpj Viruses2948-17672025-04-013111410.1038/s44298-025-00119-8A single amino acid mutation alters multiple neutralization epitopes in the respiratory syncytial virus fusion glycoproteinAhmed K. Oraby0Aleksandra Stojic1Farah Elawar2Leanne M. Bilawchuk3Ryley D. McClelland4Kaci Erwin5Madison J. Granoski6Cameron D. Griffiths7Justin D. Frederick8Elena Arutyunova9M. Joanne Lemieux10Frederick. G. West11Octavio Ramilo12Asuncion Mejias13Jason S. McLellan14David J. Marchant15Department of Medical Microbiology and ImmunologyDepartment of Medical Microbiology and ImmunologyDepartment of Medical Microbiology and ImmunologyDepartment of Medical Microbiology and ImmunologyDepartment of Medical Microbiology and ImmunologyDepartment of Molecular Biosciences, The University of Texas at AustinDepartment of Medical Microbiology and ImmunologyDepartment of Biomedical Engineering, University of VirginiaDepartment of Medical Microbiology and ImmunologyDepartment of Biochemistry, University of AlbertaDepartment of Biochemistry, University of AlbertaDepartment of Chemistry, University of AlbertaCenter for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, The Ohio State University College of MedicineCenter for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, The Ohio State University College of MedicineDepartment of Molecular Biosciences, The University of Texas at AustinDepartment of Medical Microbiology and ImmunologyAbstract Respiratory syncytial virus (RSV) is the leading cause of infant hospitalization. All current RSV therapeutics, including antibody prophylaxis and adult vaccination, target the RSV fusion glycoprotein (RSV-F). The seven neutralization sites on RSV-F are highly conserved and infrequently mutate. Here, we show that a single amino acid mutation at position 305 in RSV-F significantly alters antigenic recognition of RSV-F binding sites and reduces the susceptibility of RSV to neutralizing antibodies. In an in vitro evolution assay, we show that RSV-F L305I occurs in a majority of RSV quasi-species. Computational modeling predicted that the L305I mutation altered the epitope landscape of RSV-F, resulting in changes to neutralizing antibody sensitivity and affinity towards the RSV-F glycoprotein. Screening of published RSV-F sequences revealed that position 305 in RSV-F was conserved with a leucine and isoleucine in RSV-A and RSV-B subtypes respectively. Our study suggests that select amino acids in RSV-F may act as ‘conformational switches’ for RSV to evade host serum antibodies. This work has important implications in understanding RSV evolution and resistance as it suggests that mutational resistance to neutralizing antibodies can occur at sites distal to antigenic epitopes, significantly altering antibody sensitivity to viral infection. These unique antigenic landscape changes should be considered in the context of vaccine and therapeutic development in order to better understand viral mechanisms of evasion and resistance.https://doi.org/10.1038/s44298-025-00119-8 |
| spellingShingle | Ahmed K. Oraby Aleksandra Stojic Farah Elawar Leanne M. Bilawchuk Ryley D. McClelland Kaci Erwin Madison J. Granoski Cameron D. Griffiths Justin D. Frederick Elena Arutyunova M. Joanne Lemieux Frederick. G. West Octavio Ramilo Asuncion Mejias Jason S. McLellan David J. Marchant A single amino acid mutation alters multiple neutralization epitopes in the respiratory syncytial virus fusion glycoprotein npj Viruses |
| title | A single amino acid mutation alters multiple neutralization epitopes in the respiratory syncytial virus fusion glycoprotein |
| title_full | A single amino acid mutation alters multiple neutralization epitopes in the respiratory syncytial virus fusion glycoprotein |
| title_fullStr | A single amino acid mutation alters multiple neutralization epitopes in the respiratory syncytial virus fusion glycoprotein |
| title_full_unstemmed | A single amino acid mutation alters multiple neutralization epitopes in the respiratory syncytial virus fusion glycoprotein |
| title_short | A single amino acid mutation alters multiple neutralization epitopes in the respiratory syncytial virus fusion glycoprotein |
| title_sort | single amino acid mutation alters multiple neutralization epitopes in the respiratory syncytial virus fusion glycoprotein |
| url | https://doi.org/10.1038/s44298-025-00119-8 |
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