Structural conservation of Lassa virus glycoproteins and recognition by neutralizing antibodies

Perrett, H. R.; Brouwer, P. J. M.; Hurtado, J.; Newby, M. L.; Burger, J. A.; Liu, L.; Bouhuijs, J. H.; Gibson, G.; Messmer, T.; Schieffelin, J. S.; Antanasijevic, A.; Boons, G.-J.; Crispin, M.; Sanders, R. W.; Briney, B.; Ward, A. B.

doi:10.1101/2022.09.26.509601

bioRxiv · 10.1101/2022.09.26.509601

Structural conservation of Lassa virus glycoproteins and recognition by neutralizing antibodies

Perrett, H. R.·Brouwer, P. J. M.·Hurtado, J.·Newby, M. L.·Burger, J. A.·Liu, L.·Bouhuijs, J. H.·Gibson, G.·Messmer, T.·Schieffelin, J. S.·Antanasijevic, A.·Boons, G.-J.·Crispin, M.·Sanders, R. W.·Briney, B.·Ward, A. B.

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Abstract

SummaryLassa fever is an acute hemorrhagic fever caused by the zoonotic Lassa virus (LASV). The LASV glycoprotein complex (GPC) mediates viral entry and is the sole target for neutralizing antibodies. Immunogen design is complicated by the metastable nature of recombinant GPCs and the antigenic differences amongst LASV lineages. Despite the sequence diversity of GPC, structures of most lineages are lacking. We present the development and characterization of prefusion-stabilized, trimeric GPCs of LASV lineages II, V, and VI, revealing structural conservation despite sequence diversity. High-resolution structures and biophysical characterization of GPC in complex with GP1-A antibodies reveal their neutralization mechanisms. Finally, we present the isolation and characterization of a novel trimer-preferring neutralizing antibody belonging to the GPC-B competition group with an epitope that spans adjacent protomers and includes the fusion peptide. Our work provides molecular detail information on LASV antigenic diversity and will guide efforts to design pan-LASV vaccines. HighlightsO_LIStructural characterization of soluble glycoproteins from four Lassa virus lineages. C_LIO_LIMAb 12.1F, belonging to the GP1-A cluster, inhibits matriglycan and LAMP-1 binding. C_LIO_LIGP1-A mAbs show glycan-dependence with 19.7E demonstrating lineage-dependent binding. C_LIO_LIA novel trimer-preferring NAb S370.7 targets the GPC-B epitope. C_LI

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Perrett, H. R., Brouwer, P. J. M., Hurtado, J., Newby, M. L., Burger, J. A., Liu, L., Bouhuijs, J. H., Gibson, G., Messmer, T., Schieffelin, J. S., Antanasijevic, A., Boons, G.-J., Crispin, M., Sanders, R. W., Briney, B., Ward, A. B.. 2022-09-27. Structural conservation of Lassa virus glycoproteins and recognition by neutralizing antibodies. https://doi.org/10.1101/2022.09.26.509601

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