Human antibody C10 neutralizes by diminishing Zika but enhancing dengue virus dynamics

The human monoclonal antibody (HmAb) C10 potently cross-neutralizes Zika virus (ZIKV) and dengue virus. Analysis of antibody fragment (Fab) C10 interactions with ZIKV and dengue virus serotype 2 (DENV2) particles by cryoelectron microscopy (cryo-EM) and amide hydrogen/deuterium exchange mass spectrometry (HDXMS) shows that Fab C10 binding decreases overall ZIKV particle dynamics, whereas with DENV2, the same Fab causes increased dynamics. Testing of different Fab C10:DENV2 E protein molar ratios revealed that, at higher Fab ratios, especially at saturated concentrations, the Fab enhanced viral dynamics (detected by HDXMS), and observation under cryo-EM showed increased numbers of distorted particles. Our results suggest that Fab C10 stabilizes ZIKV but that with DENV2 particles, high Fab C10 occupancy promotes E protein dimer conformational changes leading to overall increased particle dynamics and distortion of the viral surface. This is the first instance of a broadly neutralizing antibody eliciting virus-specific increases in whole virus particle dynamics. [Display omitted] •Different mechanisms of dengue and Zika neutralization by monoclonal antibody C10•C10 stabilizes Zika but enhances dynamics of dengue virions•Dengue presents a dynamic, nonuniform epitope landscape for C10•C10 elicits differential dynamics at various stoichiometric ratios Structural analysis of the human monoclonal antibody C10, which shows strong neutralization of Zika virus and dengue virus, reveals differential effects on viral dynamics and, consequentially, distinct mechanisms of action.