Antibody 8ANC195 reveals a site of broad vulnerability on the HIV-1 envelope spike.
Antibody 8ANC195 reveals a site of broad vulnerability on the HIV-1 envelope spike.
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DOI：
10.1016/j.celrep.2014.04.001
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发表时间：
2014-05-08
期刊：
影响因子：
8.8
通讯作者：
Bjorkman PJ
中科院分区：
文献类型：
--
作者：
Scharf L;Scheid JF;Lee JH;West AP Jr;Chen C;Gao H;Gnanapragasam PN;Mares R;Seaman MS;Ward AB;Nussenzweig MC;Bjorkman PJ
抗HIV-1包膜糖蛋白(Env)的广谱中和抗体(BNAbs)可预防动物模型感染。特征化的bNAb靶点，尽管对疫苗和治疗策略至关重要，但目前是有限的。我们通过X射线结晶学和电子显微镜解析了bNAb 8ANC195与单体gp120的络合结构和三聚体Env的结构，确定了一个新的易损部位。该位点包括部分gp41和与gp120上的CD4结合位点相邻的N-连接糖链，使8ANC195成为第一个供体来源的抗HIV-1 bNAb，其表位横跨两个Env亚基。8ANC195不是使用单个可变区CDR环来穿透多糖屏蔽层，而是将其整个重链可变区插入到一个间隙中，形成与gp120糖链和gp120内部结构域的大界面，而不是与其他bNAbs接触的区域。通过分离额外的8ANC195克隆变异体，我们确定了一个更有效的变异体，这可能对使用具有非重叠表位的bNAb组合的治疗方法有价值。
Broadly neutralizing antibodies (bNAbs) to HIV-1 envelope glycoprotein (Env) can prevent infection in animal models. Characterized bNAb targets, although key to vaccine and therapeutic strategies, are currently limited. We defined a new site of vulnerability by solving structures of bNAb 8ANC195 complexed with monomeric gp120 by X-ray crystallography and trimeric Env by electron microscopy. The site includes portions of gp41 and N-linked glycans adjacent to the CD4 binding site on gp120, making 8ANC195 the first donor-derived anti-HIV-1 bNAb with an epitope spanning both Env subunits. Rather than penetrating the glycan shield using a single variable region CDR loop, 8ANC195 inserted its entire heavy chain variable domain into a gap to form a large interface with gp120 glycans and regions of the gp120 inner domain not contacted by other bNAbs. By isolating additional 8ANC195 clonal variants, we identified a more potent variant, which may be valuable for therapeutic approaches using bNAb combinations with non-overlapping epitopes.