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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-12, Vol.116 (50), p.25057-25067
• Main Authors: Avanzato, Victoria A., Oguntuyo, Kasopefoluwa Y., Escalera-Zamudio, Marina, Gutierrez, Bernardo, Golden, Michael, Pond, Sergei L. Kosakovsky, Pryce, Rhys, Walter, Thomas S., Seow, Jeffrey, Doores, Katie J., Pybus, Oliver G., Munster, Vincent J., Lee, Benhur, Bowden, Thomas A.
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - metabolism; Antibody response; Biological Sciences; Cell adhesion; Cell fusion; Cell Line, Tumor; Epitopes; F protein; Glycoproteins; Glycosylation; HEK293 Cells; Hendra Virus - chemistry; Hendra Virus - immunology; Hendra Virus - metabolism; Hendra Virus - physiology; Humans; Immune response; Immune system; Membrane fusion; Membranes; Models, Molecular; Monoclonal antibodies; Neutralization; Nipah virus; Protein Binding; Proteins; Respiratory diseases; Structural analysis; Viral Fusion Proteins - chemistry; Viral Fusion Proteins - immunology; Viral Fusion Proteins - metabolism; Virus Internalization; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1912503116

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.