Structural basis of broadly neutralizing human antibodies targeting diverse dengue virus forms.

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Abstract
Dengue virus (DENV) is a global health threat, with four antigenically distinct serotypes impeding vaccine and therapeutic development. We describe here, structural features of patient-derived, heavy chain driven Edimer recognizing (HEDR) antibodies that achieve potent, pan-serotype activity by binding a conserved quaternary epitope on DENVs envelope (E) glycoprotein dimer. Single-particle cryoEM structures of three HEDR broadly neutralizing antibodies (bnAbs) complexed to DENV delineate epitope engagement via E-glycoprotein fusion loop region and conserved glycans. We also identify capsule-shaped DENV, with helical cryoEM reconstructions of Fab-bound tubular DENV from different strains revealing that the E-glycoprotein arrangement is determined by virus strain, not bnAb identity. Our findings elucidate key binding features of HEDR bnAbs and signify the need for intervention strategies capable of neutralizing diverse DENV morphologies.

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