Structural insights into the neutralization mechanism of a higher primate antibody against dengue virus
Structural insights into the neutralization mechanism of a higher primate antibody against dengue virus
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DOI：
10.1038/emboj.2011.439
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发表时间：
2012-02-01
期刊：
影响因子：
11.4
通讯作者：
Rey, Felix A.
中科院分区：
文献类型：
--
作者：
Cockburn, Joseph J. B.;Sanchez, M. Erika Navarro;Rey, Felix A.
登革病毒的四种血清型（DENV - 1至 - 4）引发了最重要的新兴病毒性疾病。E蛋白是主要的病毒包膜糖蛋白，在病毒进入细胞过程中介导病毒膜与内体膜的融合，并且是中和抗体的作用靶点。然而，尽管对疫苗研发很重要，但强效中和人源抗体的表位尚未被描述。黑猩猩单克隆抗体5H2通过与E蛋白的结构域I结合，有效地中和DENV - 4。5H2的Fab段与DENV - 4的E蛋白结合的晶体结构显示，抗体结合阻止了E蛋白融合发卡结构的形成，再结合体外实验，证明5H2通过阻断内体中的膜融合来发挥中和作用。此外，我们发现从DENV - 4感染康复患者的人血清中含有与结构域I上的5H2表位区域结合的抗体。因此，这项研究为预防登革热疾病的有效疫苗设计提供了新的信息和工具。《欧洲分子生物学组织杂志》（2012年）31卷，767 - 779页。doi:10.1038/emboj.2011.439；2011年12月2日在线发表
The four serotypes of dengue virus (DENV-1 to -4) cause the most important emerging viral disease. Protein E, the principal viral envelope glycoprotein, mediates fusion of the viral and endosomal membranes during virus entry and is the target of neutralizing antibodies. However, the epitopes of strongly neutralizing human antibodies have not been described despite their importance to vaccine development. The chimpanzee Mab 5H2 potently neutralizes DENV-4 by binding to domain I of E. The crystal structure of Fab 5H2 bound to E from DENV-4 shows that antibody binding prevents formation of the fusogenic hairpin conformation of E, which together with in-vitro assays, demonstrates that 5H2 neutralizes by blocking membrane fusion in the endosome. Furthermore, we show that human sera from patients recovering from DENV-4 infection contain antibodies that bind to the 5H2 epitope region on domain I. This study, thus, provides new information and tools for effective vaccine design to prevent dengue disease. The EMBO Journal (2012) 31, 767-779. doi: 10.1038/emboj.2011.439; Published online 2 December 2011