Structure of Simian Immunodeficiency Virus Envelope Spikes Bound with CD4 and Monoclonal Antibody 36D5
Structure of Simian Immunodeficiency Virus Envelope Spikes Bound with CD4 and Monoclonal Antibody 36D5
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DOI：
10.1128/jvi.00134-17
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发表时间：
2017-08-01
影响因子：
5.4
通讯作者：
Taylor, Kenneth A.
中科院分区：
文献类型：
--
作者：
Hu, Guiqing;Liu, Jun;Taylor, Kenneth A.
人类免疫缺陷病毒1型（HIV-1）/猴免疫缺陷病毒（SIV）包膜刺突（Env）介导病毒进入宿主细胞。Env三聚体的gp 120组分的V3环有助于辅助受体结合位点，并且是中和抗体的靶标。我们使用冷冻电子断层扫描来可视化CD 4和V3环单克隆抗体（MAb）36 D5与SIV Env三聚体的gp 120的结合。我们的研究结果表明，36 D5结合gp 120在V3环的基础上，并建议抗体发挥其中和作用，通过阻断辅助受体结合位点。当CD 4被结合时，抗体在不改变闭合和打开状态之间的尖峰运动的动力学的情况下做到这一点。36 D5和SIV gp 120之间的相互作用类似于一些广泛中和的抗V3环抗体和HIV-1 gp 120之间的相互作用。揭示了与CD 4结合的gp 120的两种构象，表明配体Env三聚体的内在动力学性质。CD 4结合显著增加了36 D5与完整Env三聚体中gp 120的结合，这与CD 4诱导的gp 120构象和抗体结合位点的变化一致。MAb 36 D5的结合不会实质上改变两种CD 4结合构象的比例。MAb 36 D5在V3碱基的位置在构象之间变化很小，表明V3碱基在这两种状态之间的转换过程中起着枢轴点的作用。重要性SIV和HIV表面上的糖蛋白刺突是免疫系统中和抗体的唯一靶点。刺突通过表面上的厚多糖层（聚糖屏障）和掩蔽表位构象的刺突结构域之间的运动的组合来逃避免疫系统。使用SIV病毒粒子的尖峰“装饰”的主要细胞受体（CD 4）和抗体（36 D5）的辅助受体结合位点的一部分，我们可视化多种构象捕获的快速冷冻步骤，这是分离使用统计分析。我们的研究结果表明，CD 4诱导的构象动力学的刺突增强抗体的结合。
The human immunodeficiency virus type 1 (HIV-1)/simian immunodeficiency virus (SIV) envelope spike (Env) mediates viral entry into host cells. The V3 loop of the gp120 component of the Env trimer contributes to the coreceptor binding site and is a target for neutralizing antibodies. We used cryo-electron tomography to visualize the binding of CD4 and the V3 loop monoclonal antibody (MAb) 36D5 to gp120 of the SIV Env trimer. Our results show that 36D5 binds gp120 at the base of the V3 loop and suggest that the antibody exerts its neutralization effect by blocking the coreceptor binding site. The antibody does this without altering the dynamics of the spike motion between closed and open states when CD4 is bound. The interaction between 36D5 and SIV gp120 is similar to the interaction between some broadly neutralizing anti-V3 loop antibodies and HIV-1 gp120. Two conformations of gp120 bound with CD4 are revealed, suggesting an intrinsic dynamic nature of the liganded Env trimer. CD4 binding substantially increases the binding of 36D5 to gp120 in the intact Env trimer, consistent with CD4-induced changes in the conformation of gp120 and the antibody binding site. Binding by MAb 36D5 does not substantially alter the proportions of the two CD4-bound conformations. The position of MAb 36D5 at the V3 base changes little between conformations, indicating that the V3 base serves as a pivot point during the transition between these two states.IMPORTANCE Glycoprotein spikes on the surfaces of SIV and HIV are the sole targets available to the immune system for antibody neutralization. Spikes evade the immune system by a combination of a thick layer of polysaccharide on the surface (the glycan shield) and movement between spike domains that masks the epitope conformation. Using SIV virions whose spikes were "decorated" with the primary cellular receptor (CD4) and an antibody (36D5) at part of the coreceptor binding site, we visualized multiple conformations trapped by the rapid freezing step, which were separated using statistical analysis. Our results show that the CD4-induced conformational dynamics of the spike enhances binding of the antibody.