Zhao Haiyan, Fernandez Estefania, Dowd Kimberly A, Speer Scott D, Platt Derek J, Gorman Matthew J, Govero Jennifer, Nelson Christopher A, Pierson Theodore C, Diamond Michael S, Fremont Daved H
Department of Pathology & Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Cell. 2016 Aug 11;166(4):1016-1027. doi: 10.1016/j.cell.2016.07.020. Epub 2016 Jul 27.
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.
孕期感染寨卡病毒（ZIKV）已成为一个全球公共卫生问题，因为它能够引发严重的先天性疾病。在此，我们研发了六种抗寨卡病毒的小鼠单克隆抗体（mAb），其中四种（ZV - 48、ZV - 54、ZV - 64和ZV - 67）对寨卡病毒具有特异性，并能不同程度地中和非洲、亚洲和美洲毒株的感染。对Fab片段和单链抗体（scFv）进行的X射线晶体学和竞争结合分析确定了包膜蛋白结构域III（DIII）中三个空间上不同的表位，分别对应外侧脊（ZV - 54和ZV - 67）、C - C'环（ZV - 48和ZV - 64）以及ABDE片层（ZV - 2）区域。体内被动转移研究揭示了DIII外侧脊特异性中和单克隆抗体在寨卡病毒感染小鼠模型中的保护活性。我们的结果表明，DIII可被多种具有不同中和活性的型特异性抗体靶向，这为开发用于孕期的预防性抗体或设计针对寨卡病毒的表位特异性疫苗提供了途径。
