Lee Jeong Hyun, Leaman Daniel P, Kim Arthur S, Torrents de la Peña Alba, Sliepen Kwinten, Yasmeen Anila, Derking Ronald, Ramos Alejandra, de Taeye Steven W, Ozorowski Gabriel, Klein Florian, Burton Dennis R, Nussenzweig Michel C, Poignard Pascal, Moore John P, Klasse Per Johan, Sanders Rogier W, Zwick Michael B, Wilson Ian A, Ward Andrew B
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery (CAVD), The Scripps Research Institute, La Jolla California 92037, USA.
Nat Commun. 2015 Sep 25;6:8167. doi: 10.1038/ncomms9167.
The recent identification of three broadly neutralizing antibodies (bnAbs) against gp120-gp41 interface epitopes has expanded the targetable surface on the HIV-1 envelope glycoprotein (Env) trimer. By using biochemical, biophysical and computational methods, we map the previously unknown trimer epitopes of two related antibodies, 3BC315 and 3BC176. A cryo-EM reconstruction of a soluble Env trimer bound to 3BC315 Fab at 9.3 Å resolution reveals that the antibody binds between two gp41 protomers, and neutralizes the virus by accelerating trimer decay. In contrast, bnAb 35O22 binding to a partially overlapping quaternary epitope at the gp120-gp41 interface does not induce decay. A conserved gp41-proximal glycan at N88 was also shown to play a role in the binding kinetics of 3BC176 and 3BC315. Finally, our data suggest that the dynamic structure of the Env trimer influences exposure of bnAb epitopes.
最近鉴定出的三种针对gp120 - gp41界面表位的广泛中和抗体（bnAbs），扩大了HIV - 1包膜糖蛋白（Env）三聚体上的可靶向表面。通过使用生化、生物物理和计算方法，我们绘制了两种相关抗体3BC315和3BC176以前未知的三聚体表位。以9.3 Å分辨率对与3BC315 Fab结合的可溶性Env三聚体进行的冷冻电镜重建显示，该抗体结合在两个gp41原体之间，并通过加速三聚体衰变来中和病毒。相比之下，bnAb 35O22与gp120 - gp41界面处部分重叠的四级表位结合不会诱导衰变。N88处保守的靠近gp41的聚糖也被证明在3BC176和3BC315的结合动力学中起作用。最后，我们的数据表明Env三聚体的动态结构影响bnAb表位的暴露。
