The mechanism of differential neutralization of dengue serotype 3 strains by monoclonal antibody 8A1.
The mechanism of differential neutralization of dengue serotype 3 strains by monoclonal antibody 8A1.
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单克隆抗体8A1对登革热血清型3株的差异中和机制。
DOI：
10.1016/j.virol.2013.01.022
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Messer,WilliamB
中科院分区：
文献类型：
--
作者：
Zhou,Yang;Austin,SKyle;Fremont,DavedH;Yount,BoydL;Huynh,JeremyP;deSilva,AravindaM;Baric,RalphS;Messer,WilliamB
虽然以前的研究已经证明登革病毒(DENV)不同基因型之间的包膜(E)糖蛋白变异可以影响抗体的中和效力，但可变中和的机制仍然不完全清楚。在这里，我们表征了DENV-3EDIII结合的小鼠mAb8a1的表位抗体相互作用，该mAb8a1对DENV-3型具有高度可变的中和活性。利用DENV-3反向遗传学平台，我们表征了8a1结合和中和自然产生的DENV-3E基因变异病毒的能力。将单个和多个氨基酸突变引入亲本克隆背景中表明，EDIII上301和383位的突变导致了8a1差异中和表型。酶联免疫吸附试验和表面等离子共振(SPR)研究表明，结合的差异是可变中和的原因。第301位的变异主要通过影响抗体-EDIII的解离速率来决定结合差异。我们的发现与关注DENV EDIII作为疫苗靶点的许多小组相关。
While previous studies have demonstrated that envelope (E) glycoprotein variation between dengue viruses (DENV) genotypes can influence antibody neutralization potency, the mechanisms of variable neutralization remain incompletely understood. Here we characterize epitope antibody interactions of a DENV-3 EDIII binding mouse mAb 8A1 which displays highly variable neutralizing activity against DENV-3 genotypes. Using a DENV-3 reverse genetics platform, we characterize ability of 8A1 to bind and neutralize naturally occurring DENV-3 E genotypic variant viruses. Introduction of single and multiple amino acid mutations into the parental clone background demonstrates that mutations at positions 301 and 383 on EDIII are responsible for 8A1 differential neutralization phenotypes. ELISA and surface plasmon resonance (SPR) studies indicate differences in binding are responsible for the variable neutralization. Variability at position 301 primarily determined binding difference through influencing antibody-EDIII dissociation rate. Our findings are relevant to many groups focusing on DENV EDIII as a vaccine target.