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Molecular rationale for hantavirus neutralization by a reservoir host-derived monoclonal antibody

By Ilona Rissanen, Robert Stass, Stefanie A. Krumm, Jeffrey Seow, Ruben J.G. Hulswit, Guido C. Paesen, Jussi Hepojoki, Olli Vapalahti, Åke Lundkvist, Olivier Reynard, Viktor Volchkov, Katie J. Doores, Juha T Huiskonen, Thomas A Bowden

Posted 18 Apr 2020
bioRxiv DOI: 10.1101/2020.04.17.029876

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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