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

Proc Natl Acad Sci U S A. 2019 Dec 10;116(50):25057-25067. doi: 10.1073/pnas.1912503116. Epub 2019 Nov 25.


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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing* / chemistry
  • Antibodies, Neutralizing* / immunology
  • Antibodies, Neutralizing* / metabolism
  • Cell Line, Tumor
  • Glycosylation
  • HEK293 Cells
  • Hendra Virus* / chemistry
  • Hendra Virus* / immunology
  • Hendra Virus* / metabolism
  • Hendra Virus* / physiology
  • Humans
  • Models, Molecular
  • Protein Binding
  • Viral Fusion Proteins* / chemistry
  • Viral Fusion Proteins* / immunology
  • Viral Fusion Proteins* / metabolism
  • Virus Internalization*


  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Viral Fusion Proteins

Associated data

  • PDB/6T3F