Double Lock of a Human Neutralizing and Protective Monoclonal Antibody Targeting the Yellow Fever Virus Envelope
Double Lock of a Human Neutralizing and Protective Monoclonal Antibody Targeting the Yellow Fever Virus Envelope
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针对黄热病病毒包膜的人中和保护性单克隆抗体的双重锁定
DOI：
10.1016/j.celrep.2018.12.065
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发表时间：
2019-01-08
期刊：
影响因子：
8.8
通讯作者：
Gao, George F.
中科院分区：
文献类型：
--
作者：
Lu, Xishan;Xiao, Haixia;Gao, George F.
黄热病病毒（YFV）是一种致命的人类病原体，是黄病毒属的原型。最近，YFV在非洲和巴西重新出现，导致数百人死亡，其中一些病例输入到中国。迫切需要预防或治疗对策。此前，已通过噬菌体展示技术筛选出几种抗YFV的人单克隆抗体。在这里，我们发现其中一种5A具有较高的中和效力和良好的保护作用。YFV包膜(E)蛋白在融合前和融合后的结晶学分析显示其构象与其他黄病毒E蛋白相似。此外，在两种状态下，5A与E蛋白复合物的结构都被分解，揭示了一个不变的识别位点。结构分析和功能数据表明，5A具有很高的中和效力，因为它通过阻止病毒附着和融合来干扰病毒进入。这些发现将有助于免疫原或抑制剂的设计。
Yellow fever virus (YFV), a deadly human pathogen, is the prototype of the genus Flavivirus. Recently, YFV re-emerged in Africa and Brazil, leading to hundreds of deaths, with some cases imported to China. Prophylactic or therapeutic countermeasures are urgently needed. Previously, several human monoclonal antibodies against YFV were screened out by phage display. Here, we find that one of them, 5A, exhibits high neutralizing potency and good protection. Crystallographic analysis of the YFV envelope (E) protein in its pre- and post-fusion states shows conformations similar to those observed in other E proteins of flaviviruses. Furthermore, the structures of 5A in complex with the E protein in both states are resolved, revealing an invariant recognition site. Structural analysis and functional data suggest that 5A has high neutralization potency because it interferes with virus entry by preventing both virus attachment and fusion. These findings will be instrumental for immunogen or inhibitor design.