Structural and molecular basis for Ebola virus neutralization by protective human antibodies.
Structural and molecular basis for Ebola virus neutralization by protective human antibodies.
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保护性人类抗体中和埃博拉病毒的结构和分子基础
DOI：
10.1126/science.aad6117
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发表时间：
2016-03-18
期刊：
影响因子：
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通讯作者：
McLellan JS
中科院分区：
文献类型：
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作者：
Misasi J;Gilman MS;Kanekiyo M;Gui M;Cagigi A;Mulangu S;Corti D;Ledgerwood JE;Lanzavecchia A;Cunningham J;Muyembe-Tamfun JJ;Baxa U;Graham BS;Xiang Y;Sullivan NJ;McLellan JS
抗体阻止埃博拉病毒进入西非最近爆发的埃博拉病毒表明，需要一种有效的疫苗和疗法来治疗感染者。Corti等人从1995年基奎特爆发的幸存者中分离出两种单克隆抗体，并证明了它们在埃博拉病毒感染的猕猴中的治疗效果。事实上，一种抗体在感染后5天内给予猕猴保护。Misasi等人解决了与埃博拉病毒糖蛋白（GP）结合的两种抗体片段的晶体结构，GP介导病毒进入细胞。这两种抗体针对GP的不同区域，但在两种情况下都阻断了病毒进入所需的步骤。科学，这个问题。1339和1343结构分析揭示了两种单克隆抗体如何阻止埃博拉病毒进入细胞。埃博拉病毒引起出血热，病死率很高，目前还没有批准的治疗方法。两种人单克隆抗体mAb100和mAb114联合使用可保护非人灵长类动物免受埃博拉病毒病的所有症状，包括病毒血症。在这里，我们证明了单克隆抗体100识别埃博拉病毒糖蛋白（GP）三聚体的基础上，闭塞访问组织蛋白酶切割环，并防止病毒进入所需的GP的蛋白水解切割。我们发现，单克隆抗体114与糖帽和内部圣杯的GP相互作用，保持关联后，蛋白水解去除的糖帽，并抑制切割GP结合其受体。这些结果定义了两种保护性抗体的中和基础，并可能促进治疗和疫苗的开发。
Antibodies block Ebola virus entry The recent Ebola virus outbreak in West Africa illustrates the need for both an effective vaccine and therapies to treat infected individuals. Corti et al. isolated two monoclonal antibodies from a survivor of the 1995 Kikwit outbreak and demonstrated their therapeutic efficacy in Ebola virus–infected macaques. In fact, one antibody protected macaques when it was given up to 5 days after infection. Misasi et al. solved the crystal structures of fragments of the two antibodies bound to the Ebola virus glycoprotein (GP), which mediates viral cell entry. The two antibodies targeted different regions of GP, but in both cases blocked steps required for viral entry. Science, this issue pp. 1339 & 1343 Structural analysis reveals how two monoclonal antibodies block access of Ebola virus into cells. Ebola virus causes hemorrhagic fever with a high case fatality rate for which there is no approved therapy. Two human monoclonal antibodies, mAb100 and mAb114, in combination, protect nonhuman primates against all signs of Ebola virus disease, including viremia. Here, we demonstrate that mAb100 recognizes the base of the Ebola virus glycoprotein (GP) trimer, occludes access to the cathepsin-cleavage loop, and prevents the proteolytic cleavage of GP that is required for virus entry. We show that mAb114 interacts with the glycan cap and inner chalice of GP, remains associated after proteolytic removal of the glycan cap, and inhibits binding of cleaved GP to its receptor. These results define the basis of neutralization for two protective antibodies and may facilitate development of therapies and vaccines.