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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A human monoclonal antibody neutralizes diverse HIV-1 isolates by binding a critical gp41 epitope.
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A human monoclonal antibody neutralizes diverse HIV-1 isolates by binding a critical gp41 epitope.

机译：人类单克隆抗体通过结合关键的gp41表位中和各种HIV-1分离株。

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摘要

HIV-1 entry into cells is mediated by the envelope glycoprotein receptor-binding (gp120) and membrane fusion-promoting (gp41) subunits. The gp41 heptad repeat 1 (HR1) domain is the molecular target of the fusion-inhibitor drug enfuvirtide (T20). The HR1 sequence is highly conserved and therefore considered an attractive target for vaccine development, but it is unknown whether antibodies can access HR1. Herein, we use gp41-based peptides to select a human antibody, 5H/I1-BMV-D5 (D5), that binds to HR1 and inhibits the assembly of fusion intermediates in vitro. D5 inhibits the replication of diverse HIV-1 clinical isolates and therefore represents a previously unknown example of a crossneutralizing IgG selected by binding to designed antigens. NMR studies and functional analyses map the D5-binding site to a previously identified hydrophobic pocket situated in the HR1 groove. This hydrophobic pocket was proposed as a drug target and subsequently identified as a common binding site for peptide and peptidomimetic fusion inhibitors. The finding that the D5 fusion-inhibitory antibody shares the same binding site suggests that the hydrophobic pocket is a "hot spot" for fusion inhibition and an ideal target on which to focus a vaccine-elicited antibody response. Our data provide a structural framework for the design of new immunogens and therapeutic antibodies with crossneutralizing potential.
机译：HIV-1进入细胞是由包膜糖蛋白受体结合（gp120）和促进膜融合的亚基（gp41）介导的。 gp41七肽重复序列1（HR1）域是融合抑制剂药物恩夫韦肽（T20）的分子靶标。 HR1序列高度保守，因此被认为是疫苗开发的有吸引力的靶标，但尚不清楚抗体是否可以进入HR1。在本文中，我们使用基于gp41的肽来选择人抗体5H / I1-BMV-D5（D5），该抗体与HR1结合并在体外抑制融合中间体的组装。 D5抑制了多种HIV-1临床分离株的复制，因此代表了通过与设计抗原结合而选择的交叉中和IgG的未知实例。 NMR研究和功能分析将D5结合位点映射到位于HR1凹槽中的先前确定的疏水口袋。该疏水口袋被提议作为药物靶标，随后被鉴定为肽和拟肽融合抑制剂的共同结合位点。 D5融合抑制抗体共享相同的结合位点的发现表明，疏水口袋是融合抑制的“热点”，也是将疫苗引发的抗体应答聚焦的理想靶标。我们的数据为设计具有交叉中和潜力的新型免疫原和治疗性抗体提供了结构框架。

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