DENGUE VIRUS. Cryo-EM structure of an antibody that neutralizes dengue virus type 2 by locking E protein dimers.
DENGUE VIRUS. Cryo-EM structure of an antibody that neutralizes dengue virus type 2 by locking E protein dimers.
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DOI：
10.1126/science.aaa8651
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发表时间：
2015-07-03
期刊：
影响因子：
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通讯作者：
Lok SM
中科院分区：
文献类型：
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作者：
Fibriansah G;Ibarra KD;Ng TS;Smith SA;Tan JL;Lim XN;Ooi JS;Kostyuchenko VA;Wang J;de Silva AM;Harris E;Crowe JE Jr;Lok SM
登革热病毒（DENV）有四种紧密相关的血清型。感染一种血清型会产生抗体，这些抗体可能会发生交叉反应，并在二次感染中增强其他血清型的感染。我们证明，登革热病毒2型（DENV2）特异性人单克隆抗体（HMAb）2D22在抗体增强型重症登革热疾病的小鼠模型中具有治疗作用。我们确定了HMAb 2D22与两种不同的DENV2毒株结合的冷冻电镜（cryo - EM）结构。HMAb 2D22在二聚体结构中与病毒包膜（E）蛋白结合，这可能阻断了病毒融合所需的E蛋白重组。根据毒株的不同，HMAb 2D22会“锁定”病毒表面三分之二或全部的二聚体，但对这些DENV2毒株具有同等的中和效力。由HMAb 2D22确定的表位是疫苗和治疗方法的一个潜在靶点。
There are four closely-related dengue virus (DENV) serotypes. Infection with one serotype generates antibodies that may cross-react and enhance infection with other serotypes in a secondary infection. We demonstrated that DENV serotype 2 (DENV2)–specific human monoclonal antibody (HMAb) 2D22 is therapeutic in a mouse model of antibody-enhanced severe dengue disease. We determined the cryo–electron microscopy (cryo-EM) structures of HMAb 2D22 complexed with two different DENV2 strains. HMAb 2D22 binds across viral envelope (E) proteins in the dimeric structure, which probably blocks the E protein reorganization required for virus fusion. HMAb 2D22 “locks” two-thirds of or all dimers on the virus surface, depending on the strain, but neutralizes these DENV2 strains with equal potency. The epitope defined by HMAb 2D22 is a potential target for vaccines and therapeutics.