Molecular rationale for hantavirus neutralization by a reservoir host-derived monoclonal antibody
Stefanie A. Krumm,
Ruben J.G. Hulswit,
Guido C. Paesen,
Katie J. Doores,
Juha T Huiskonen,
Thomas A Bowden
Posted 18 Apr 2020
bioRxiv DOI: 10.1101/2020.04.17.029876
Posted 18 Apr 2020
The intricate lattice of Gn and Gc glycoprotein spike complexes at the surface of hantaviruses facilitates host-cell entry and is the primary target of the neutralizing antibody-mediated immune response. Here, through study of a neutralizing monoclonal antibody (mAb 4G2) generated in a bank vole reservoir host following infection with Puumala virus (PUUV), we provide molecular-level insights into how antibody-mediated targeting of the hantaviral glycoprotein lattice effectively neutralizes the virus. Crystallographic analysis reveals that mAb 4G2 binds to a multi-domain site on Gc in the pre-fusion state, and that Fab binding is incompatible with the conformational changes of the Gc that are required for host cell entry. Cryo-electron microscopy of PUUV-like particles treated with Fab 4G2 demonstrates that the antibody binds to monomeric Gc at breaks in the Gn-Gc lattice, highlighting the immunological accessibility of Gc monomers on the mature hantavirus surface and the plastic nature of the higher-order lattice assembly. This work provides a structure-based blueprint for rationalizing antibody-mediated targeting of hantaviruses. ### Competing Interest Statement The authors have declared no competing interest.
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