Structure of HCMV glycoprotein B in the postfusion conformation bound to a neutralizing human antibody.
Structure of HCMV glycoprotein B in the postfusion conformation bound to a neutralizing human antibody.
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DOI：
10.1038/ncomms9176
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发表时间：
2015-09-14
影响因子：
16.6
通讯作者：
Carfi A
中科院分区：
文献类型：
--
作者：
Chandramouli S;Ciferri C;Nikitin PA;Caló S;Gerrein R;Balabanis K;Monroe J;Hebner C;Lilja AE;Settembre EC;Carfi A
人类巨细胞病毒 (HCMV) 对免疫功能低下的个体和子宫内感染的新生儿构成重大威胁。糖蛋白 B (gB) 是疱疹病毒融合蛋白，因其在感染中不可或缺的作用而成为中和抗体的靶标和候选疫苗。在这里，我们展示了与 1G2 的 Fab 片段结合的 HCMV gB 胞外域的晶体结构，1G2 是一种从血清阳性受试者中分离出来的中和人单克隆抗体。 gB/1G2 相互作用主要由 1G2 重链 CDR3 中的芳香残基突出到 gB 抗原结构域 5 (AD-5) 的疏水裂口中。结构分析以及与 HSV gB 的比较表明 HCMV gB 上存在额外的中和抗体结合位点。最后，免疫沉淀实验表明，1G2 可以与 HCMV 病毒体 gB 结合，表明其表位在病毒表面暴露并可接近。我们的数据将支持针对 HCMV 感染的疫苗和治疗性抗体的开发。 巨细胞病毒对免疫系统受损的个体和子宫内感染的新生儿构成危险。在这里，作者展示了中和抗体结合的病毒融合蛋白糖蛋白 B 的结构，支持治疗性抗体和疫苗的开发。
Human cytomegalovirus (HCMV) poses a significant threat to immunocompromised individuals and neonates infected in utero. Glycoprotein B (gB), the herpesvirus fusion protein, is a target for neutralizing antibodies and a vaccine candidate due to its indispensable role in infection. Here we show the crystal structure of the HCMV gB ectodomain bound to the Fab fragment of 1G2, a neutralizing human monoclonal antibody isolated from a seropositive subject. The gB/1G2 interaction is dominated by aromatic residues in the 1G2 heavy chain CDR3 protruding into a hydrophobic cleft in the gB antigenic domain 5 (AD-5). Structural analysis and comparison with HSV gB suggest the location of additional neutralizing antibody binding sites on HCMV gB. Finally, immunoprecipitation experiments reveal that 1G2 can bind to HCMV virion gB suggesting that its epitope is exposed and accessible on the virus surface. Our data will support the development of vaccines and therapeutic antibodies against HCMV infection. Cytomegalovirus is a danger to individuals with compromised immune systems and neonates infected in utero. Here the authors show the structure of a neutralizing antibody-bound viral fusion protein glycoprotein B, supporting the development of therapeutic antibodies and vaccines.