Guenaga Javier, Garces Fernando, de Val Natalia, Stanfield Robyn L, Dubrovskaya Viktoriya, Higgins Brett, Carrette Barbara, Ward Andrew B, Wilson Ian A, Wyatt Richard T
IAVI Neutralizing Antibody Center at The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Immunity. 2017 May 16;46(5):792-803.e3. doi: 10.1016/j.immuni.2017.04.014.
Advances in HIV-1 envelope glycoprotein (Env) design generate native-like trimers and high-resolution clade A, B, and G structures and elicit neutralizing antibodies. However, a high-resolution clade C structure is critical, as this subtype accounts for the majority of HIV infections worldwide, but well-ordered clade C Env trimers are more challenging to produce due to their instability. Based on targeted glycine substitutions in the Env fusion machinery, we defined a general approach that disfavors helical transitions leading to post-fusion conformations, thereby favoring the pre-fusion state. We generated a stabilized, soluble clade C Env (16055 NFL) and determined its crystal structure at 3.9 Å. Its overall conformation is similar to SOSIP.664 and native Env trimers but includes a covalent linker between gp120 and gp41, an engineered 201-433 disulfide bond, and density corresponding to 22 N-glycans. Env-structure-guided design strategies resulted in multiple homogeneous cross-clade immunogens with the potential to advance HIV vaccine development.
HIV-1包膜糖蛋白（Env）设计方面的进展产生了类似天然的三聚体以及高分辨率的A、B和G亚型结构，并引发了中和抗体。然而，高分辨率的C亚型结构至关重要，因为该亚型占全球HIV感染的大多数，但由于C亚型Env三聚体不稳定，产生结构有序的三聚体更具挑战性。基于Env融合机制中的靶向甘氨酸取代，我们定义了一种通用方法，该方法不利于导致融合后构象的螺旋转变，从而有利于融合前状态。我们生成了一种稳定的、可溶性的C亚型Env（16055 NFL），并确定了其3.9埃的晶体结构。其整体构象与SOSIP.664和天然Env三聚体相似，但包括gp120和gp41之间的共价连接、一个工程化的201-433二硫键以及对应于22个N-聚糖的密度。基于Env结构的设计策略产生了多种均质的跨亚型免疫原，有可能推动HIV疫苗的开发。
