Structural basis of West Nile virus neutralization by a therapeutic antibody.
Structural basis of West Nile virus neutralization by a therapeutic antibody.
复制标题
DOI：
10.1038/nature03956
复制
发表时间：
2005-09-29
期刊：
影响因子：
64.8
通讯作者：
Fremont DH
中科院分区：
文献类型：
--
作者：
Nybakken GE;Oliphant T;Johnson S;Burke S;Diamond MS;Fremont DH
西尼罗河病毒与人类流行的登革热、黄热病和日本脑炎病毒密切相关。对一种特别有效的单抗的研究，即使在感染后5天给药，也能够保护小鼠免受致命的西尼罗河病毒攻击，这为病毒中和的结构基础提供了重要的信息。这项工作突出了病毒包膜蛋白的III区，作为治疗性抗体和疫苗的潜在靶点。本文的在线版本(doi：10.1038/Nature03956)包含补充材料，授权用户可以使用。西尼罗河病毒是一种蚊媒黄病毒，与人类疫情密切相关，可引起登革热、黄热病和日本脑炎病毒。在确定感染的过程中，这些二十面体病毒经历了由可能的受体结合结构域III(DIII)的包膜糖蛋白重排和疏水融合环的暴露所催化的内体膜融合。体液免疫在西尼罗河病毒感染早期具有重要的保护作用。在这里，我们研究了特异性结合DIII的E16单抗的中和机制。在结构上，E16抗体Fab片段包含16个残基，位于DIII的四个环上，这是一个在西尼罗河病毒中保守的共识中和表位序列，在其他黄病毒中是不同的。E16表位在三种不同的环境中从成熟病毒粒子的表面突出，对接研究预测Fab结合将使五倍的簇状表位暴露。我们还表明，E16主要在病毒附着后的一个步骤抑制感染，可能是通过阻止包膜糖蛋白构象的变化。综上所述，我们的结果表明，针对优势DIII表位的疫苗策略可能会引发针对黄病毒疾病的安全有效的免疫反应。本文的在线版本(doi：10.1038/Nature03956)包含补充材料，授权用户可以使用。
West Nile virus is closely related to the human epidemic-causing dengue, yellow fever and Japanese encephalitis viruses. The study of a particularly effective monoclonal antibody, capable of protecting mice from lethal West Nile virus challenge even if administered 5 days after infection, has provided important information on the structural basis of viral neutralization. The work highlights the domain III region of the viral envelope protein as a potential target for both therapeutic antibodies and vaccines. The online version of this article (doi:10.1038/nature03956) contains supplementary material, which is available to authorized users. West Nile virus is a mosquito-borne flavivirus closely related to the human epidemic-causing dengue, yellow fever and Japanese encephalitis viruses. In establishing infection these icosahedral viruses undergo endosomal membrane fusion catalysed by envelope glycoprotein rearrangement of the putative receptor-binding domain III (DIII) and exposure of the hydrophobic fusion loop. Humoral immunity has an essential protective function early in the course of West Nile virus infection. Here, we investigate the mechanism of neutralization by the E16 monoclonal antibody that specifically binds DIII. Structurally, the E16 antibody Fab fragment engages 16 residues positioned on four loops of DIII, a consensus neutralizing epitope sequence conserved in West Nile virus and distinct in other flaviviruses. The E16 epitope protrudes from the surface of mature virions in three distinct environments, and docking studies predict Fab binding will leave five-fold clustered epitopes exposed. We also show that E16 inhibits infection primarily at a step after viral attachment, potentially by blocking envelope glycoprotein conformational changes. Collectively, our results suggest that a vaccine strategy targeting the dominant DIII epitope may elicit safe and effective immune responses against flaviviral diseases. The online version of this article (doi:10.1038/nature03956) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
3.7
作者：
Hiramatsu, K;Tadano, M;Lai, CJ
通讯作者：
Lai, CJ
开发具有针对西尼罗河病毒的治疗潜力的人源化单克隆抗体。
影响因子：
82.9
作者：
Oliphant, Theodore;Engle, Michael;Nybakken, Grant E;Doane, Chris;Johnson, Syd;Huang, Ling;Gorlatov, Sergey;Mehlhop, Erin;Marri, Anantha;Chung, Kyung Min;Ebel, Gregory D;Kramer, Laura D;Fremont, Daved H;Diamond, Michael S
通讯作者：
Diamond, Michael S
影响因子：
64.8
作者：
Modis, Y;Ogata, S;Harrison, SC
通讯作者：
Harrison, SC
影响因子：
64.8
作者：
HALSTEAD, SB;OROURKE, EJ
通讯作者：
OROURKE, EJ
二维VOPBA揭示了层粘连蛋白受体（LAMR1）与登革热病毒血清型1、2和3的相互作用。
影响因子：
4.8
作者：
Tio, Phaik Hooi;Jong, Wan Wui;Cardosa, Mary Jane
通讯作者：
Cardosa, Mary Jane