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Human antibody C10 neutralizes by diminishing Zika but enhancing dengue virus dynamics
Cell ( IF 45.5 ) Pub Date : 2021-11-30 , DOI: 10.1016/j.cell.2021.11.009
Xin-Xiang Lim 1 , Bo Shu 2 , Shuijun Zhang 2 , Aaron W K Tan 2 , Thiam-Seng Ng 2 , Xin-Ni Lim 2 , Valerie S-Y Chew 2 , Jian Shi 3 , Gavin R Screaton 4 , Shee-Mei Lok 5 , Ganesh S Anand 6
Affiliation  

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.



中文翻译:


人类抗体 C10 通过减少寨卡病毒但增强登革热病毒动态来中和



人单克隆抗体 (HmAb) C10 可有效交叉中和寨卡病毒 (ZIKV) 和登革热病毒。通过冷冻电子显微镜 (cryo-EM) 和酰胺氢/氘交换质谱 (HDXMS) 对抗体片段 (Fab) C10 与 ZIKV 和登革热病毒血清型 2 (DENV2) 颗粒的相互作用进行分析,结果表明 Fab C10 结合会降低总体 ZIKV 颗粒动力学,而对于 DENV2,相同的 Fab 会导致动态增加。对不同 Fab C10:DENV2 E 蛋白摩尔比的测试表明,在较高的 Fab 比率下,尤其是在饱和浓度下,Fab 增强了病毒动力学(通过 HDXMS 检测),并且冷冻电镜下的观察显示扭曲颗粒数量增加。我们的结果表明,Fab C10 可以稳定 ZIKV,但对于 DENV2 颗粒,Fab C10 的高占有率会促进 E 蛋白二聚体构象变化,从而导致颗粒动力学总体增加和病毒表面变形。这是广泛中和抗体引起整个病毒颗粒动力学的病毒特异性增加的第一个实例。

更新日期:2021-12-09
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