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A broadly protective antibody that targets the flavivirus NS1 protein
Science ( IF 56.9 ) Pub Date : 2021-01-07 , DOI: 10.1126/science.abb9425
Naphak Modhiran 1 , Hao Song 2, 3 , Lidong Liu 4 , Cheryl Bletchly 5 , Lou Brillault 1, 6 , Alberto A Amarilla 1 , Xiaoying Xu 2 , Jianxun Qi 2 , Yan Chai 2 , Stacey T M Cheung 1 , Renee Traves 1 , Yin Xiang Setoh 1 , Summa Bibby 1 , Connor A P Scott 1 , Morgan E Freney 1 , Natalee D Newton 1 , Alexander A Khromykh 1 , Keith J Chappell 1 , David A Muller 1 , Katryn J Stacey 1 , Michael J Landsberg 1 , Yi Shi 2 , George F Gao 2, 3 , Paul R Young 1 , Daniel Watterson 1
Affiliation  

Two antibodies against flaviviruses Flaviviruses are a group of RNA viruses that include the human pathogens dengue virus, Zika virus, and West Nile virus. The envelope protein (E) on the virus surface has been the target of vaccine development, but problems have arisen with antibodies against E, leading to enhanced infection. Now, Modhiran et al. and Biering et al. describe two different antibodies that bind to the flavivirus NS1 protein and prevent it from disrupting epithelial cells, which is associated with severe disease. Both antibodies cross-react with multiple flavivirus NS1 proteins. The antibodies reduce viremia and increase survival in mouse models of flavivirus disease. Both papers include structures of NS1 bound to an antibody, which give insight into the protective mechanism. Science, this issue p. 190, p. 194 Broadly protective antibodies that target the flavivirus NS1 protein are structurally and functionally characterized. There are no approved flaviviral therapies and the development of vaccines against flaviruses has the potential of being undermined by antibody-dependent enhancement (ADE). The flavivirus nonstructural protein 1 (NS1) is a promising vaccine antigen with low ADE risk but has yet to be explored as a broad-spectrum therapeutic antibody target. Here, we provide the structural basis of NS1 antibody cross-reactivity through cocrystallization of the antibody 1G5.3 with NS1 proteins from dengue and Zika viruses. The 1G5.3 antibody blocks multi-flavivirus NS1-mediated cell permeability in disease-relevant cell lines, and therapeutic application of 1G5.3 reduces viremia and improves survival in dengue, Zika, and West Nile virus murine models. Finally, we demonstrate that 1G5.3 protection is independent of effector function, identifying the 1G5.3 epitope as a key site for broad-spectrum antiviral development.

中文翻译:

一种针对黄病毒 NS1 蛋白的广泛保护性抗体

针对黄病毒的两种抗体 黄病毒是一组 RNA 病毒,包括人类病原体登革热病毒、寨卡病毒和西尼罗河病毒。病毒表面的包膜蛋白 (E) 一直是疫苗开发的目标,但针对 E 的抗体出现了问题,导致感染增强。现在,Modhiran 等人。和比林等人。描述了两种不同的抗体,它们与黄病毒 NS1 蛋白结合并防止其破坏与严重疾病相关的上皮细胞。两种抗体都与多种黄病毒 NS1 蛋白发生交叉反应。在黄病毒病小鼠模型中,这些抗体可减少病毒血症并提高存活率。两篇论文都包含与抗体结合的 NS1 结构,从而深入了解保护机制。科学,这个问题 p。190,第。194 针对黄病毒 NS1 蛋白的广泛保护性抗体在结构和功能上都有特征。没有批准的黄病毒疗法,针对黄病毒的疫苗的开发有可能被抗体依赖性增强 (ADE) 所破坏。黄病毒非结构蛋白 1 (NS1) 是一种很有前景的疫苗抗原,具有低 ADE 风险,但尚未作为广谱治疗性抗体靶点进行探索。在这里,我们通过抗体 1G5.3 与来自登革热和寨卡病毒的 NS1 蛋白的共结晶,提供了 NS1 抗体交叉反应的结构基础。1G5.3 抗体可阻断疾病相关细胞系中多黄病毒 NS1 介导的细胞通透性,1G5.3 的治疗应用可减少病毒血症并提高登革热、寨卡病毒、和西尼罗河病毒小鼠模型。最后,我们证明 1G5.3 保护独立于效应子功能,将 1G5.3 表位确定为广谱抗病毒开发的关键位点。
更新日期:2021-01-07
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