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

DOI: 10.1073/pnas.1912503116

Authors: Victoria A. Avanzato (University of Oxford; National Institute of Allergy and Infectious Diseases, National Institutes of Health) , Kasopefoluwa Y. Oguntuyo (Icahn School of Medicine at Mount Sinai) , Marina Escalera-Zamudio (University of Oxford) , Bernardo Gutierrez (University of Oxford) , Michael Golden (University of Oxford) , Sergei L. Kosakovsky Pond (Temple University) , Rhys Pryce (Wellcome Centre for Human Genetics, University of Oxford) , Thomas S. Walter (Wellcome Center for Human Genetics, University of Oxford) , Jeffrey Seow (King’s College London, Guy’s Hospital) , Katie J. Doores (King’s College London, Guy’s Hospital) , Oliver G. Pybus (University of Oxford) , Vincent J. Munster (National Institute of Allergy and Infectious Diseases, National Institutes of Health) , Benhur Lee (Icahn School of Medicine at Mount Sinai) , Thomas A. Bowden (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 123

State: Published (Approved)
Published: November 2019
Diamond Proposal Number(s): 19946

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.

Journal Keywords: henipavirus; glycoprotein; structure; antibody response; viral fusion

Diamond Keywords: Henipaviruses; Nipah Virus (NiV); Viruses

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 27/11/2019 11:08

Documents:
1912503116.full.pdf

Discipline Tags:

Vaccines Pathogens Infectious Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)