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A structural basis for antibody-mediated neutralization of Nipah virus reveals a site of vulnerability at the fusion glycoprotein apex

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Victoria A Avanzato, Kasopefoluwa Y Oguntuyo, Marina Escalera-Zamudio, Bernardo Gutierrez, Michael Golden, Sergei L Kosakovsky Pond, Rhys Pryce, Thomas S Walter, Jeffrey Seow, Katie J Doores, Oliver G Pybus, Vincent J Munster, Benhur Lee, Thomas A Bowden

Original languageEnglish
Pages (from-to)25057-25067
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number50
Early online date25 Nov 2019
DOIs
Publication statusPublished - 10 Dec 2019

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Copyright © 2019 the Author(s). Published by PNAS.

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Abstract

Nipah virus (NiV) is a highly pathogenic paramyxovirus that causes frequent outbreaks of severe neurologic and respiratory disease in humans with high case fatality rates. The 2 glycoproteins displayed on the surface of the virus, NiV-G and NiV-F, mediate host-cell attachment and membrane fusion, respectively, and are targets of the host antibody response. Here, we provide a molecular basis for neutralization of NiV through antibody-mediated targeting of NiV-F. Structural characterization of a neutralizing antibody (nAb) in complex with trimeric prefusion NiV-F reveals an epitope at the membrane-distal domain III (DIII) of the molecule, a region that undergoes substantial refolding during host-cell entry. The epitope of this monoclonal antibody (mAb66) is primarily protein-specific and we observe that glycosylation at the periphery of the interface likely does not inhibit mAb66 binding to NiV-F. Further characterization reveals that a Hendra virus-F-specific nAb (mAb36) and many antibodies in an antihenipavirus-F polyclonal antibody mixture (pAb835) also target this region of the molecule. Integrated with previously reported paramyxovirus F-nAb structures, these data support a model whereby the membrane-distal region of the F protein is targeted by the antibody-mediated immune response across henipaviruses. Notably, our domain-specific sequence analysis reveals no evidence of selective pressure at this region of the molecule, suggestive that functional constraints prevent immune-driven sequence variation. Combined, our data reveal the membrane-distal region of NiV-F as a site of vulnerability on the NiV surface.

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