The binding of HIV-1 Envelope glycoproteins (Env) to host receptor CD4 exposes vulnerable conserved epitopes within the co-receptor binding site (CoRBS) which are required for the engagement of either CCR5 or CXCR4 co-receptor to allow HIV-1 entry. Antibodies against this region have been implicated in the protection against HIV acquisition in non-human primate (NHP) challenge studies and found to act synergistically with antibodies of other specificities to deliver effective Fc-mediated effector function against HIV-1-infected cells. Here, we describe the structure and function of N12-i2, an antibody isolated from an HIV-1-infected individual, and show how the unique structural features of this antibody allow for its effective Env recognition and Fc-mediated effector function. N12-i2 binds within the CoRBS utilizing two adjacent sulfo-tyrosines (TYS) for binding, one of which binds to a previously unknown TYS binding pocket formed by gp120 residues of high sequence conservation among HIV-1 strains. Structural alignment with gp120 in complex with the co-receptor CCR5 indicates that the new pocket corresponds to TYS at position 15 of CCR5. In addition, structure-function analysis of N12-i2 and other CoRBS-specific antibodies indicates a link between modes of antibody binding within the CoRBS and Fc-mediated effector activities. The efficiency of antibody-dependent cellular cytotoxicity (ADCC) correlated with both the level of antibody binding and the mode of antibody attachment to the epitope region, specifically with the way the Fc region was oriented relative to the target cell surface. Antibodies with poor Fc access mediated the poorest ADCC whereas those with their Fc region readily accessible for interaction with effector cells mediated the most potent ADCC. Our data identify a previously unknown binding site for TYS within the assembled CoRBS of the HIV-1 virus. In addition, our combined structural-modeling-functional analyses provide new insights into mechanisms of Fc-effector function of antibodies against HIV-1, in particular, how antibody binding to Env antigen affects the efficiency of ADCC response.

中文翻译：

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定义控制 HIV-1 共受体结合位点的识别和 Fc 介导的效应器功能的规则。


HIV-1 包膜糖蛋白 (Env) 与宿主受体 CD4 的结合暴露了辅助受体结合位点 (CoRBS) 内脆弱的保守表位，这些表位是 CCR5 或 CXCR4 辅助受体结合以允许 HIV-1 进入所必需的。在非人灵长类动物 (NHP) 攻击研究中，针对该区域的抗体与防止 HIV 感染有关，并发现其与其他特异性抗体协同作用，可针对 HIV-1 感染的细胞提供有效的 Fc 介导的效应功能。在这里，我们描述了 N12-i2（一种从 HIV-1 感染个体中分离出来的抗体）的结构和功能，并展示了该抗体的独特结构特征如何实现其有效的 Env 识别和 Fc 介导的效应功能。 N12-i2 在 CoRBS 内结合，利用两个相邻的磺基酪氨酸 (TYS) 进行结合，其中一个与先前未知的 TYS 结合袋结合，该结合袋由 HIV-1 毒株中序列高度保守的 gp120 残基形成。与共受体 CCR5 复合的 gp120 的结构比对表明新口袋对应于 CCR5 位置 15 的 TYS。此外，N12-i2 和其他 CoRBS 特异性抗体的结构功能分析表明 CoRBS 内抗体结合模式与 Fc 介导的效应子活性之间的联系。抗体依赖性细胞毒性 (ADCC) 的效率与抗体结合水平和抗体附着到表位区域的模式相关，特别是与 Fc 区域相对于靶细胞表面的定向方式相关。 Fc 通路较差的抗体介导最差的 ADCC，而 Fc 区域易于与效应细胞相互作用的抗体介导最有效的 ADCC。 我们的数据确定了 HIV-1 病毒组装的 CoRBS 中 TYS 的一个先前未知的结合位点。此外，我们的结构-建模-功能相结合的分析为抗HIV-1抗体的Fc效应器功能机制提供了新的见解，特别是抗体与Env抗原的结合如何影响ADCC反应的效率。