Structural basis for the neutralization of hepatitis E virus by a cross-genotype antibody
Structural basis for the neutralization of hepatitis E virus by a cross-genotype antibody
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跨基因型抗体中和戊型肝炎病毒的结构基础。
DOI：
10.1038/cr.2015.34
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发表时间：
2015-05-01
期刊：
影响因子：
44.1
通讯作者：
Sivaraman, J.
中科院分区：
文献类型：
--
作者：
Gu, Ying;Tang, Xuhua;Sivaraman, J.
戊型肝炎病毒（HEV）是一种无包膜、正义、单链RNA病毒，是肠道肝炎的主要原因。 HEV属于肝炎病毒科，包含四种基因型（基因型1-4），属于单一血清型。我们描述了一种单克隆抗体 (mAb) 8G12，它同样识别 HEV 的所有四种基因型，具有相似的 2.53-3.45 nM 结合亲和力。 mAb 8G12具有保护、中和能力，可以显着阻断病毒对宿主细胞的感染。基因型 1、3 和 4 的动物研究证实了 8G12 的跨基因型中和能力及其对戊型肝炎的有效预防。分别以 4.0 和 2.3 埃的分辨率确定了具有丰富基因型 1 和 4 的 HEV E2s 结构域（病毒衣壳最突出的区域）的 8G12 的复杂晶体结构。这些结构表明 8G12 通过 E2s 二聚化区域中的表位识别这两种基因型。基于结构的诱变和使用病毒样颗粒的细胞模型测定鉴定了几个对于 8G12 中和至关重要的保守残基（Glu549、Lys554 和 Gly591）。此外，8G12表位被确定为参与病毒-宿主相互作用的关键表位。这些发现将有助于制定预防最常见的 HEV 感染的通用策略。
Hepatitis E virus (HEV), a non-enveloped, positive-sense, single-stranded RNA virus, is a major cause of enteric hepatitis. Classified into the family Hepeviridae, HEV comprises four genotypes (genotypes 1-4), which belong to a single serotype. We describe a monoclonal antibody (mAb), 8G12, which equally recognizes all four genotypes of HEV, with similar to 2.53-3.45 nM binding affinity. The mAb 8G12 has a protective, neutralizing capacity, which can significantly block virus infection in host cells. Animal studies with genotypes 1, 3 and 4 confirmed the cross-genotype neutralizing capacity of 8G12 and its effective prevention of hepatitis E disease. The complex crystal structures of 8G12 with the HEV E2s domain (the most protruded region of the virus capsid) of the abundant genotypes 1 and 4 were determined at 4.0 and 2.3 angstrom resolution, respectively. These structures revealed that 8G12 recognizes both genotypes through the epitopes in the E2s dimerization region. Structure-based mutagenesis and cell-model assays with virus-like particles identified several conserved residues (Glu549, Lys554 and Gly591) that are essential for 8G12 neutralization. Moreover, the epitope of 8G12 is identified as a key epitope involved in virus-host interactions. These findings will help develop a common strategy for the prevention of the most abundant form of HEV infection.