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.
Highlights
The prototypic henipaviruses (HNVs), Hendra and Nipah virus, are highly pathogenic paramyxoviruses that have the potential to cause severe neurologic and respiratory disease in humans [1]
Structural Characterization of Nipah virus (NiV)-F in Complex with fragment of mAb66 (Fab66). mAb66 is a monoclonal antibody that neutralizes NiV through recognition of NiV-F and was derived by DNA immunization of rabbits with expression plasmids encoding NiV-M, codon optimized NiV-F and NiV-G, and soluble NiV-G derived from the reference Malaysia strain (SI Appendix, Table S1) [42, 43]. mAb66 neutralizes NiV-F/G mediated viral entry and fusion with an IC50 of
To determine the molecular basis for mAb66mediated neutralization, we rescued the sequence of the corresponding Fab fragment of mAb66 (Fab66)
Summary
The prototypic henipaviruses (HNVs), Hendra and Nipah virus, are highly pathogenic paramyxoviruses that have the potential to cause severe neurologic and respiratory disease in humans [1]. Since 2001, Bangladesh and India have experienced regular NiV outbreaks [6,7,8], with the recent 2018 NiV outbreak in Kerala, India, exhibiting a 91% case fatality rate [9] Both HNVs circulate in reservoir host Pteropus bat populations [10, 11] and can cause spillover events into human populations through amplifying hosts, such as pigs and horses, or directly from bats, principally through the consumption of contaminated date palm sap [8]. Despite causing regular outbreaks with high case fatality rates, there are currently no licensed vaccines or therapeutics for Nipah virus (NiV) infection. We sought to determine the molecular basis for how the antibody response neutralizes NiV by targeting the surface-displayed fusion glycoprotein, NiV-F. The structure of a potent NiV and HeV cross-reactive nAb (m102.3) bound to HeV-G shows that the mechanism of neutralization involves occlusion of the receptor-binding site [41]
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