A human monoclonal antibody neutralizes diverse HIV-1 isolates by binding a critical gp41 epitope
A human monoclonal antibody neutralizes diverse HIV-1 isolates by binding a critical gp41 epitope
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DOI：
10.1073/pnas.0506927102
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发表时间：
2005-10-11
影响因子：
11.1
通讯作者：
Pessi, A
中科院分区：
文献类型：
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作者：
Miller, MD;Geleziunas, R;Pessi, A
HIV-1进入细胞是由包膜糖蛋白受体结合（gp120）和膜融合促进（gp41）亚基介导的。gp41七肽重复1 （HR1）结构域是融合抑制剂药物恩福韦肽（T20）的分子靶点。HR1序列是高度保守的，因此被认为是疫苗开发的一个有吸引力的靶点，但抗体是否能接近HR1尚不清楚。在此，我们使用基于gp41的肽选择了一种人抗体5H/I1-BMV-DS (D5)，该抗体与HR1结合并在体外抑制融合中间体的组装。D5抑制多种HIV-1临床分离株的复制，因此代表了一个以前未知的通过结合设计抗原选择交叉中和IgG的例子。核磁共振研究和功能分析将d5结合位点映射到先前确定的位于HR1槽中的疏水口袋。这个疏水口袋被提出作为药物靶点，随后被确定为肽和拟肽融合抑制剂的共同结合位点。D5融合抑制抗体具有相同的结合位点，这一发现表明疏水袋是融合抑制的“热点”，也是疫苗引发抗体反应的理想靶点。我们的数据为设计新的免疫原和具有交叉中和电位的治疗性抗体提供了一个结构框架。
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-DS (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 an 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.