Misasi John, Gilman Morgan S A, Kanekiyo Masaru, Gui Miao, Cagigi Alberto, Mulangu Sabue, Corti Davide, Ledgerwood Julie E, Lanzavecchia Antonio, Cunningham James, Muyembe-Tamfun Jean Jacques, Baxa Ulrich, Graham Barney S, Xiang Ye, Sullivan Nancy J, McLellan Jason S
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Division of Infectious Diseases, Boston Children's Hospital, Boston, MA 02215, USA.
Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
Science. 2016 Mar 18;351(6279):1343-6. doi: 10.1126/science.aad6117. Epub 2016 Feb 25.
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.
埃博拉病毒可引发出血热，病死率很高，目前尚无获批的治疗方法。两种人源单克隆抗体，即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所有症状的影响，并包括病毒血症。在此，我们证明mAb100识别埃博拉病毒糖蛋白（GP）三聚体的基部，封闭组织蛋白酶切割环的通道，并阻止病毒进入所需的GP蛋白水解切割。我们表明mAb114与GP的聚糖帽和内部杯状结构相互作用，在聚糖帽被蛋白水解去除后仍保持结合，并抑制切割后的GP与其受体的结合。这些结果确定了两种保护性抗体的中和基础，并可能促进治疗方法和疫苗的开发。
