Zolla-Pazner Susan, Cohen Sandra Sharpe, Boyd David, Kong Xiang-Peng, Seaman Michael, Nussenzweig Michel, Klein Florian, Overbaugh Julie, Totrov Max
Veterans Affairs New York Harbor Healthcare System, New York, New York, USA Departments of Pathology and Biochemistry, New York University School of Medicine, New York, New York, USA
Departments of Pathology and Biochemistry, New York University School of Medicine, New York, New York, USA.
J Virol. 2015 Oct 21;90(2):636-49. doi: 10.1128/JVI.01645-15. Print 2016 Jan 15.
Antibodies (Abs) specific for the V3 loop of the HIV-1 gp120 envelope neutralize most tier 1 and many tier 2 viruses and are present in essentially all HIV-infected individuals as well as immunized humans and animals. Vaccine-induced V3 Abs are associated with reduced HIV infection rates in humans and affect the nature of transmitted viruses in infected vaccinees, despite the fact that V3 is often occluded in the envelope trimer. Here, we link structural and experimental data showing how conformational alterations of the envelope trimer render viruses exceptionally sensitive to V3 Abs. The experiments interrogated the neutralization sensitivity of pseudoviruses with single amino acid mutations in various regions of gp120 that were predicted to alter packing of the V3 loop in the Env trimer. The results indicate that the V3 loop is metastable in the envelope trimer on the virion surface, flickering between states in which V3 is either occluded or available for binding to chemokine receptors (leading to infection) and to V3 Abs (leading to virus neutralization). The spring-loaded V3 in the envelope trimer is easily released by disruption of the stability of the V3 pocket in the unliganded trimer or disruption of favorable V3/pocket interactions. Formation of the V3 pocket requires appropriate positioning of the V1V2 domain, which is, in turn, dependent on the conformation of the bridging sheet and on the stability of the V1V2 B-C strand-connecting loop.
The levels of antibodies to the third variable region (V3) of the HIV envelope protein correlate with reduced HIV infection rates. Previous studies showed that V3 is often occluded, as it sits in a pocket of the envelope trimer on the surface of virions; however, the trimer is flexible, allowing occluded portions of the envelope (like V3) to flicker into an exposed position that binds antibodies. Here we provide a systematic interrogation of mechanisms by which single amino acid changes in various regions of gp120 (i) render viruses sensitive to neutralization by V3 antibodies, (ii) result in altered packing of the V3 loop, and (iii) activate an open conformation that exposes V3 to the effects of V3 Abs. Taken together, these and previous studies explain how V3 antibodies can protect against HIV-1 infection and why they should be one of the targets of vaccine-induced antibodies.
针对HIV-1 gp120包膜V3环的抗体（Abs）可中和大多数1级和许多2级病毒，并且基本上存在于所有HIV感染者以及免疫后的人和动物体内。疫苗诱导的V3 Abs与人类HIV感染率降低相关，并影响感染疫苗者体内传播病毒的特性，尽管V3在包膜三聚体中常常被遮蔽。在此，我们将结构数据与实验数据联系起来，展示了包膜三聚体的构象改变如何使病毒对V3 Abs异常敏感。这些实验研究了在gp120各个区域具有单个氨基酸突变的假病毒的中和敏感性，这些突变预计会改变Env三聚体中V3环的堆积。结果表明，V3环在病毒体表面的包膜三聚体中是亚稳态的，在V3被遮蔽或可用于结合趋化因子受体（导致感染）和V3 Abs（导致病毒中和）的状态之间闪烁。包膜三聚体中弹簧加载的V3很容易通过破坏未结合配体的三聚体中V3口袋的稳定性或破坏有利的V3/口袋相互作用而释放。V3口袋的形成需要V1V2结构域的适当定位，而这又依赖于桥接片的构象以及V1V2 B-C链连接环的稳定性。
针对HIV包膜蛋白第三可变区（V3）的抗体水平与HIV感染率降低相关。先前的研究表明，V3常常被遮蔽，因为它位于病毒体表面包膜三聚体的一个口袋中；然而，三聚体是灵活的，使得包膜的被遮蔽部分（如V3）能够闪烁到一个可结合抗体的暴露位置。在此，我们对gp120各个区域的单个氨基酸变化导致病毒对V3抗体中和敏感、导致V3环堆积改变以及激活使V3暴露于V3 Abs作用的开放构象的机制进行了系统研究。综上所述，这些研究以及先前的研究解释了V3抗体如何预防HIV-1感染，以及它们为何应成为疫苗诱导抗体的靶标之一。
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