Epitope dampening monotypic measles virus hemagglutinin glycoprotein results in resistance to cocktail of monoclonal antibodies.
Epitope dampening monotypic measles virus hemagglutinin glycoprotein results in resistance to cocktail of monoclonal antibodies.
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DOI：
10.1371/journal.pone.0052306
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Nara PL
中科院分区：
文献类型：
--
作者：
Lech PJ;Tobin GJ;Bushnell R;Gutschenritter E;Pham LD;Nace R;Verhoeyen E;Cosset FL;Muller CP;Russell SJ;Nara PL
麻疹病毒（MV）是血清单型的。麻疹一次发作或接种MV疫苗后可获得终身免疫力。这与流感病毒相反，流感病毒很容易对免疫系统产生抵抗力并复发。更好地了解将MV限制在一种血清型的因素可能使我们能够预测MV在未来是否会保持单型，并影响新型MV疫苗和治疗方法的设计。MV血凝素（H）糖蛋白与细胞受体结合，随后触发融合（F）糖蛋白将病毒融合到细胞中。H也是中和抗体的主要靶标。为了探索MV是否由于缺乏H糖蛋白的可塑性而保持单型，我们使用免疫抑制技术产生具有合理设计的N-连接糖基化位点和不同表位突变的病毒，并筛选逃避单克隆抗体（mAb）的病毒。然后，我们将合理设计的突变与自然选择的突变相结合，以产生对同时靶向四个不同表位的中和mAb的混合物具有抗性的病毒。两个表位通过工程化的N-连接的糖基化保护，并且两个表位在mAb存在下通过两轮连续的人工选择获得逃逸突变。这些表位中的三个被已知干扰受体结合的mAb靶向。结果表明，在分析的表位内，H可以耐受不同残基中的突变和额外的N-连接糖基化以逃避mAb。理解H可以耐受的变化程度是重要的，因为我们跟踪其在宿主中的进化，所述宿主的免疫力是由基因型A菌株而不是多种遗传上不同的野生型MV诱导的疫苗。
The measles virus (MV) is serologically monotypic. Life-long immunity is conferred by a single attack of measles or following vaccination with the MV vaccine. This is contrary to viruses such as influenza, which readily develop resistance to the immune system and recur. A better understanding of factors that restrain MV to one serotype may allow us to predict if MV will remain monotypic in the future and influence the design of novel MV vaccines and therapeutics. MV hemagglutinin (H) glycoprotein, binds to cellular receptors and subsequently triggers the fusion (F) glycoprotein to fuse the virus into the cell. H is also the major target for neutralizing antibodies. To explore if MV remains monotypic due to a lack of plasticity of the H glycoprotein, we used the technology of Immune Dampening to generate viruses with rationally designed N-linked glycosylation sites and mutations in different epitopes and screened for viruses that escaped monoclonal antibodies (mAbs). We then combined rationally designed mutations with naturally selected mutations to generate a virus resistant to a cocktail of neutralizing mAbs targeting four different epitopes simultaneously. Two epitopes were protected by engineered N-linked glycosylations and two epitopes acquired escape mutations via two consecutive rounds of artificial selection in the presence of mAbs. Three of these epitopes were targeted by mAbs known to interfere with receptor binding. Results demonstrate that, within the epitopes analyzed, H can tolerate mutations in different residues and additional N-linked glycosylations to escape mAbs. Understanding the degree of change that H can tolerate is important as we follow its evolution in a host whose immunity is vaccine induced by genotype A strains instead of multiple genetically distinct wild-type MVs.
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影响因子：
16.8
作者：
Hashiguchi, Takao;Ose, Toyoyuki;Yanagi, Yusuke
通讯作者：
Yanagi, Yusuke
影响因子：
5.4
作者：
Duprex, WP;McQuaid, S;Rima, BK
通讯作者：
Rima, BK
影响因子：
3.7
作者：
Hadac, EM;Peng, KW;Russell, SJ
通讯作者：
Russell, SJ
影响因子：
2.2
作者：
Gans, HA;Yasukawa, LL;Arvin, AM
通讯作者：
Arvin, AM
麻疹病毒血凝素：对细胞进入的结构见解和麻疹疫苗。
影响因子：
5.2
作者：
Hashiguchi T;Maenaka K;Yanagi Y
通讯作者：
Yanagi Y