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

Rissanen, I.; Stass, R.; Krumm, S. A.; Seow, J.; Hulswit, R. J. G.; Paesen, G. C.; Hepojoki, J.; Vapalahti, O.; Lundkvist, A.; Reynard, O.; Volchkov, V.; Doores, K. J.; Huiskonen, J. T.; Bowden, T. A.

doi:10.1101/2020.04.17.029876

bioRxiv · 10.1101/2020.04.17.029876

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

Rissanen, I.·Stass, R.·Krumm, S. A.·Seow, J.·Hulswit, R. J. G.·Paesen, G. C.·Hepojoki, J.·Vapalahti, O.·Lundkvist, A.·Reynard, O.·Volchkov, V.·Doores, K. J.·Huiskonen, J. T.·Bowden, T. A.

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Abstract

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.

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Rissanen, I., Stass, R., Krumm, S. A., Seow, J., Hulswit, R. J. G., Paesen, G. C., Hepojoki, J., Vapalahti, O., Lundkvist, A., Reynard, O., Volchkov, V., Doores, K. J., Huiskonen, J. T., Bowden, T. A.. 2020-04-18. Molecular rationale for hantavirus neutralization by a reservoir host-derived monoclonal antibody. https://doi.org/10.1101/2020.04.17.029876

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