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

Journal article

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.

Authors: Avanzato, V; Oguntuyo, K; Escalera-Zamudio, M; Gutierrez, B; Golden, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: National Academy of Sciences
• Journal: Proceedings of the National Academy of Sciences
• Volume: 116
• Issue: 50
• Pages: 25057-25067
• Publication date: 2019-11-25
• Acceptance date: 2019-10-30
• DOI: 10.1073/pnas.1912503116
• EISSN: 1091-6490
• ISSN: 0027-8424
• Pmid: 31767754
• Language: English
• Keywords: viral fusion; structure; antibody response; glycoprotein; FFR; henipavirus