Center for Modeling Complex Interactions, University of Idaho, Moscow, Idaho, United States of America.
Department of Biological Sciences, University of Idaho, Moscow, Idaho, United States of America.
PLoS One. 2019 Mar 21;14(3):e0211093. doi: 10.1371/journal.pone.0211093. eCollection 2019.
The 2014 outbreak of Ebola virus disease (EVD) in Western Africa is the largest recorded filovirus disease outbreak and led to the death of over 11,000 people. The recent EVD outbreaks (since May 2018) in the Democratic Republic of the Congo has already claimed the lives of over 250 people. Tackling Ebola virus (EBOV) outbreaks remains a challenge. Over the years, significant efforts have been put into developing vaccines or antibody therapies which rely on an envelope glycoprotein (GP) of Zaire ebolavirus (strain Mayinga-76). Therefore, one key approach for combating EVD epidemics is to predict mutations that may diminish the effectiveness of the treatment. In a previous study we generated a watch list of potential antibody escape mutations of EBOV GP against the monoclonal antibody KZ52. Molecular modeling methods were applied to the three-dimensional experimental structure of EBOV GP bound to KZ52 to predict the effect of every possible single mutation in EBOV GP. The final watch list contained 34 mutations that were predicted to destabilize binding of KZ52 to EBOV GP but did not affect EBOV GP folding and its ability to form trimers. In this study, we expand our watch list by including three more monoclonal antibodies with distinct epitopes on GP, namely Antibody 100 (Ab100), Antibody 114 (Ab114) and 13F6-1-2. Our updated watch list contains 127 mutations, three of which have been seen in humans or are experimentally associated with reduced efficacy of antibody treatment. We believe mutations on this watch list require attention since they provide information about circumstances in which interventions could lose the effectiveness.
2014 年在西非暴发的埃博拉病毒病（EVD）是有记录以来最大的丝状病毒病暴发，导致 11000 多人死亡。最近（自 2018 年 5 月以来）刚果民主共和国的 EVD 暴发已经导致 250 多人死亡。应对埃博拉病毒（EBOV）暴发仍然是一个挑战。多年来，人们投入了大量精力开发疫苗或抗体疗法，这些疗法依赖于扎伊尔埃博拉病毒（Mayinga-76 株）的包膜糖蛋白（GP）。因此，抗击 EVD 流行的一个关键方法是预测可能降低治疗效果的突变。在之前的研究中，我们针对单克隆抗体 KZ52 生成了埃博拉病毒 GP 潜在抗体逃逸突变的观察清单。应用分子建模方法对 EBOV GP 与 KZ52 结合的三维实验结构进行了预测，以预测 EBOV GP 中每一种可能的单点突变的影响。最终的观察清单包含 34 个突变，这些突变被预测会破坏 KZ52 与 EBOV GP 的结合，但不影响 EBOV GP 的折叠及其形成三聚体的能力。在这项研究中，我们通过包括三种针对 GP 上不同表位的单克隆抗体来扩展我们的观察清单，即抗体 100（Ab100）、抗体 114（Ab114）和 13F6-1-2。我们更新的观察清单包含 127 个突变，其中有 3 个突变已在人类中出现或与抗体治疗效果降低有关。我们认为，这个观察清单上的突变需要引起关注，因为它们提供了有关干预措施可能失去效力的情况的信息。
