Structural Basis of Zika Virus-Specific Antibody Protection.
Structural Basis of Zika Virus-Specific Antibody Protection.
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DOI：
10.1016/j.cell.2016.07.020
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发表时间：
2016-08-11
期刊：
影响因子：
64.5
通讯作者：
Fremont DH
中科院分区：
文献类型：
--
作者：
Zhao H;Fernandez E;Dowd KA;Speer SD;Platt DJ;Gorman MJ;Govero J;Nelson CA;Pierson TC;Diamond MS;Fremont DH
孕期寨卡病毒(ZIKV)感染已成为一个全球公共卫生问题，因为它能够导致严重的先天性疾病。在此，我们研制了6株抗ZIKV的鼠单抗，其中4株(ZV-48、ZV-54、ZV-和ZV-67)是ZIKV特异性的，对非洲株、亚洲株和美洲株都有不同程度的中和感染。Fab片段和ScFv的X射线结晶学和竞争结合分析在包膜蛋白DIII中确定了三个空间上不同的表位，分别对应于侧脊(ZV-54和ZV-67)、C-C‘环(ZV-48和ZV-)和ABDE折叠(ZV-2)区域。体内被动转移研究显示，在ZIKV感染的小鼠模型中，DIII-侧脊特异性中和单抗具有保护活性。我们的结果表明，DIII被多种具有不同中和活性的类型特异性抗体所靶向，这为开发用于妊娠的预防性抗体或设计针对ZIKV的表位特异性疫苗提供了途径。
Zika virus (ZIKV) infection during pregnancy has emerged as a global public health problem because of its ability to cause severe congenital disease. Here, we developed six mouse monoclonal antibodies (mAbs) against ZIKV including four (ZV-48, ZV-54, ZV-64, and ZV-67) that were ZIKV-specific and neutralized infection of African, Asian, and American strains to varying degrees. X-ray crystallographic and competition binding analyses of Fab fragments and scFvs defined three spatially distinct epitopes in DIII of the envelope protein corresponding to the lateral ridge (ZV-54 and ZV-67), C–C′ loop (ZV-48 and ZV-64), and ABDE sheet (ZV-2) regions. In vivo passive transfer studies revealed protective activity of DIII-lateral ridge specific neutralizing mAbs in a mouse model of ZIKV infection. Our results suggest that DIII is targeted by multiple type-specific antibodies with distinct neutralizing activity, which provides a path for developing prophylactic antibodies for use in pregnancy or designing epitope-specific vaccines against ZIKV.