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Functional and antigenic constraints on the Nipah virus fusion protein
Open accessPreprint — published as 10.1073/pnas.2529505123
Abstract
Nipah virus is a highly pathogenic virus in the family Paramyxoviridae that utilizes two distinct surface glycoproteins to infect cells. The receptor-binding protein (RBP) binds host receptors whereas the fusion protein (F) merges viral and host membranes. Here, we use non-replicative pseudoviruses to safely measure the effects of all F single amino-acid residue mutations on its cell entry function and neutralization by monoclonal antibodies. We compare mutational tolerance in F with previous experimental measurements for RBP and show that F is much more functionally constrained than the RBP. We also identify mutationally intolerant sites on the F trimer surface and core that are critical for proper function, and describe mutations that are candidates for stabilizing F in the prefusion conformation for vaccine design. We quantify how F mutations affect neutralization by six monoclonal antibodies, and show that the magnitude of mutational effects on neutralization varies among antibodies. Our measurements of mutational effects on Nipah virus F predict the ability of the antibodies to neutralize the related Hendra virus. Overall, our work defines the functional and antigenic constraints on the F protein from an important zoonotic virus. Importance: Nipah virus sporadically spills over into humans, where it is often fatal. The Nipah fusion (F) protein is necessary for infection, and is a target for vaccines and antibody therapies. To better understand the constraints on this protein, we experimentally measured how ∼8,500 single amino-acid mutations to F affected its function using pseudoviruses that enable the safe study of protein mutants without the generation of actual replicative virus. We examined the effects of these mutations in the context of structural data and publicly available Nipah virus sequences to characterize the constraints that shape F protein evolution. This work has implications for understanding paramyxovirus fusion proteins, and informs the development of vaccines and monoclonal antibody therapies.
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Metadata
- Authors
- Larsen, B. B., Harari, S., Gen, R., Stewart, C., Veesler, D., & Bloom, J. D.
- Affiliations
- Fred Hutch Cancer Center (US)
- University of Washington (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Bloom, Jesse D.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- openRxiv
- Published
- 2025-10-15
- Volume
- 123
- Issue
- 6
- Pages
- e2529505123-e2529505123
- ISSN
- 0027-8424 (ISSN-L)
- PMC
- PMC12885220
- OpenAlex
- W7128163174
- Cited by
- 3
- References
- 1
- Citations by year
- 2026: 3
- FWCI
- 13.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (R01AI141707, 1U19AI181881, DP1AI158186, 75N93022C00036)
- Topics
- Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › Viral Infections and Outbreaks Research
- Keywords
- Nipah virus, fusion protein, receptor binding protein, mutational tolerance, functional constraints, monoclonal antibody neutralization, pseudovirus, prefusion conformation, vaccine design, Hendra virus, zoonotic viruses
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