Structural basis of poxvirus fusion regulation and anti-A16/G9 antibody-mediated neutralization and protection

Monkeypox virus (MPXV) is a poxvirus endemic to Central and West Africa with high epidemic potential. Poxviruses enter host cells via a conserved entry-fusion complex (EFC), which mediates viral fusion to the cell membrane. The EFC is a promising therapeutic target, but the absence of structural dat...

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Detalles Bibliográficos
Autores: Meola, Annalisa, Vernuccio, Riccardo, Battini, Leandro, Albericio, Guillermo, Delgado, Pilar, Bamford, Rebecca, Pokorny, Laura, Broutin, Manon, Martínez León, Alejandro, Gallien, Sébastien, Gil, María, Noriega, María A., Guivel-Benhassine, Florence, Porrot, Françoise, Postal, Jeanne, Buchrieser, Julian, Hubert, Mathieu, Haouz, Ahmed, Lafaye, Pierre, Esteban, Mariano, Hub, Jochen S., Mahévas, Matthieu, Chappert, Pascal, Mercer, Jason, García-Arriaza, Juan, Schwartz, Olivier, Guardado-Calvo, Pablo
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/413413
Acceso en línea:http://hdl.handle.net/10261/413413
https://api.elsevier.com/content/abstract/scopus_id/105016875247
Access Level:acceso abierto
Palabra clave:Viral fusion
Entry-fusion complex
mpox
Neutralizing antibodies
Poxvirus
Serpin
Structural virology
Vaccines
Vaccinia virus
Viral entry
Descripción
Sumario:Monkeypox virus (MPXV) is a poxvirus endemic to Central and West Africa with high epidemic potential. Poxviruses enter host cells via a conserved entry-fusion complex (EFC), which mediates viral fusion to the cell membrane. The EFC is a promising therapeutic target, but the absence of structural data has limited the development of fusion-inhibiting treatments. Here, we investigated A16/G9, a subcomplex of the EFC that controls fusion timing. Using cryo-electron microscopy, we showed how A16/G9 interacts with A56/K2, a viral fusion suppressor that prevents superinfection. Immunization with A16/G9 elicited a protective immune response in mice. Using X-ray crystallography, we characterized two neutralizing antibodies and engineered a chimeric antibody that cross-neutralizes several poxviruses more efficiently than 7D11, the most potent antibody targeting the EFC described to date. These findings highlight the potential of A16/G9 as a candidate for subunit vaccines and identify regions of the EFC as targets for antiviral development.

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