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Structural basis of poxvirus fusion regulation and anti-A16/G9 antibody-mediated neutralization and protection
Annalisa Meola1, Riccardo Vernuccio1, Leandro Battini1
1Structural biology of infectious diseases G5+ unit, Institut Pasteur, Université Paris Cité, Paris, France.
Abstract:
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.
Insights
Researchers explored the monkeypox virus entry-fusion complex (EFC), identifying the A16/G9 subcomplex. This study reveals potential targets for antiviral therapies and subunit vaccines against poxviruses.
Area of Science:
- Virology
- Structural Biology
- Immunology
Background:
- Monkeypox virus (MPXV) poses a significant public health threat due to its epidemic potential.
- Poxvirus entry into host cells is mediated by a conserved entry-fusion complex (EFC).
- Limited structural data on the EFC has hindered the development of fusion-inhibiting antiviral treatments.
Purpose of the Study:
- To investigate the A16/G9 subcomplex of the MPXV EFC, which regulates viral fusion timing.
- To elucidate the structural interactions within the EFC, including its interaction with the A56/K2 fusion suppressor.
- To identify potential therapeutic targets for antiviral development and vaccine candidates.
Main Methods:
- Cryo-electron microscopy (cryo-EM) to determine the structure of the A16/G9 subcomplex and its interactions.
- X-ray crystallography to characterize neutralizing antibodies targeting the EFC.
- Immunization studies in mice to assess the immunogenicity and protective potential of A16/G9.
Main Results:
- Structural analysis revealed how A16/G9 interacts with A56/K2, a viral fusion suppressor.
- Immunization with A16/G9 induced a protective immune response in a mouse model.
- Characterization of neutralizing antibodies, including an engineered chimeric antibody with enhanced cross-neutralization capabilities against multiple poxviruses.
Conclusions:
- The A16/G9 subcomplex is a promising candidate for developing subunit vaccines against MPXV and other poxviruses.
- Specific regions of the EFC can be targeted for the development of novel antiviral therapies.
- Structural insights into the EFC pave the way for next-generation poxvirus therapeutics.
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