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Literature detail

Potent monoclonal antibody-mediated neutralization of a divergent Hendra virus variant.

Zhaoqian Wang1 Ha V Dang1 Moushimi Amaya2,3 Yan Xu4 Randy Yin2,3 Lianying Yan2,3 Andrew C Hickey3,5 Edward J Annand6,7,8,9 Bethany A Horsburgh10,11 Peter A Reid12 Ina Smith8 John-Sebastian Eden10,11 Kai Xu4 Christopher C Broder2 David Veesler1,13
Affiliations 13 institutions
  1. Department of Biochemistry, University of Washington, Seattle, WA 98195.
  2. Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD 20814.
  3. Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20814.
  4. Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210.
  5. US Public Health Services Commissioned Corps, Rockville, MD 20852.
  6. Sydney School of Veterinary Science, University of Sydney, Sydney, 2570 NSW, Australia.
  7. Sydney Institute for Infectious Diseases, University of Sydney, Sydney, 2006 NSW, Australia.
  8. Black Mountain Laboratories, Health and Biosecurity, Commonwealth Scientific and Industrial Research Organisation, Canberra, 2601 ACT, Australia.
  9. Equine Veterinary and One Health Epidemiology, EquiEpiVet, Aireys Inlet, Surf Coast, 3231 VIC, Australia.
  10. University of Sydney School of Medicine, Sydney, 2006 NSW, Australia.
  11. Westmead Institute for Medical Research, Sydney, 2145 NSW, Australia.
  12. Private Equine Veterinary Practice, Brisbane, 4034 QLD, Australia.
  13. HHMI, University of Washington, Seattle, WA 98195.
PMID 35617431 2022 Proc Natl Acad Sci U S A eng ppublish
PubMed DOI Browse context

Article

Publication summary

Hendra virus (HeV) and Nipah virus (NiV) are deadly zoonotic Henipaviruses (HNVs) responsible for recurrent outbreaks in humans and domestic species of highly fatal (50 to 95%) disease. A HeV variant (HeV-g2) of unprecedented genetic divergence has been identified in two fatally diseased horses, and in two flying fox species in regions of Australia not previously considered at risk for HeV spillover. Given the HeV-g2 divergence from HeV while retaining equivalent pathogenicity and spillover potential, understanding receptor usage and antigenic properties is urgently required to guide One Health biosecurity. Here, we show that the HeV-g2 G glycoprotein shares a conserved receptor tropism with prototypic HeV and that a panel of monoclonal antibodies recognizing the G and F glycoproteins potently neutralizes HeV-g2– and HeV G/F–mediated entry into cells. We determined a crystal structure of the Fab fragment of the hAH1.3 antibody bound to the HeV G head domain, revealing an antigenic site associated with potent cross-neutralization of both HeV-g2 and HeV. Structure-guided formulation of a tetravalent monoclonal antibody (mAb) mixture, targeting four distinct G head antigenic sites, results in potent neutralization of HeV and HeV-g2 and delineates a path forward for implementing multivalent mAb combinations for postexposure treatment of HNV infections.

antibodies Hendra virus Nipah virus receptor variants Antibodies, Monoclonal Antibodies, Neutralizing Antibodies, Viral Hendra Virus Immunoglobulin Fab Fragments Viral Envelope Proteins Crystallography, X-Ray Epitopes Humans Neutralization Tests Post-Exposure Prophylaxis Protein Domains attachment protein G

Structured evidence records

Evidence records

3 total
Molecular Adaptation 2 records
Molecular Adaptation Extraction confidence 0.80
Key finding

The G glycoprotein of the divergent Hendra virus variant HeV-g2 maintains receptor tropism equivalent to the original Hendra virus, suggesting conserved molecular determinants of host-cell entry.

Virus
HeV
Host
Not specified
Location
Not specified
Supporting text

Here, we show that the HeV-g2 G glycoprotein shares a conserved receptor tropism with prototypic HeV and that a panel of monoclonal antibodies recognizing the G and F glycoproteins potently neutralizes HeV-g2– and HeV G/F–mediated entry into cells.

Genes or proteins
G glycoprotein; F glycoprotein
Mechanism types
receptor_binding; cell_entry; tropism_conservation
Molecular Adaptation Extraction confidence 0.80
Key finding

Structural analysis revealed a conserved antigenic site on the HeV G head domain mediating cross-neutralization of HeV-g2 and the original HeV, showing molecular conservation of antibody epitopes.

Virus
HeV
Host
Not specified
Location
Not specified
Supporting text

We determined a crystal structure of the Fab fragment of the hAH1.3 antibody bound to the HeV G head domain, revealing an antigenic site associated with potent cross-neutralization of both HeV-g2 and HeV.

Genes or proteins
G glycoprotein
Mechanism types
immune_escape; antigenic_conservation
Receptor Usage 1 records
Receptor Usage Extraction confidence 0.95
Key finding

The HeV-g2 G glycoprotein uses the same receptor tropism as prototypic Hendra virus, demonstrating conserved receptor usage in cell entry.

Virus
HeV
Host
Not specified
Location
Not specified
Supporting text

Here, we show that the HeV-g2 G glycoprotein shares a conserved receptor tropism with prototypic HeV and that a panel of monoclonal antibodies recognizing the G and F glycoproteins potently neutralizes HeV-g2– and HeV G/F–mediated entry into cells.

Method
cell-entry assay; neutralization assay; structural analysis