A Universal Approach to Optimize the Folding and Stability of Prefusion-Closed HIV-1 Envelope Trimers

作者：Lucy Rutten, Yen‐Ting Lai, Sven Blokland, Daphné Truan, Ilona J. M. Bisschop, Nika M. Strokappe, Annemart Koornneef, Daniëlle van Manen, Gwo‐Yu Chuang, S. Katie Farney, Hanneke Schuitemaker, Peter D. Kwong, Johannes P. M. Langedijk · 发表于：Cell Reports · 年份：2018 · DOI：10.1016/j.celrep.2018.03.061 · 被引用次数：119 · 研究领域：HIV Research and Treatment、HIV/AIDS drug development and treatment、Bacteriophages and microbial interactions

The heavily glycosylated native-like envelope (Env) trimer of HIV-1 is expected to have low immunogenicity, whereas misfolded forms are often highly immunogenic. High-quality correctly folded Envs may therefore be critical for developing a vaccine that induces broadly neutralizing antibodies. Moreover, the high variability of Env may require immunizations with multiple Envs. Here, we report a universal strategy that provides for correctly folded Env trimers of high quality and yield through a repair-and-stabilize approach. In the repair stage, we utilized a consensus strategy that substituted rare strain-specific residues with more prevalent ones. The stabilization stage involved structure-based design and experimental assessment confirmed by crystallographic feedback. Regions important for the refolding of Env were targeted for stabilization. Notably, the α9-helix and an intersubunit β sheet proved to be critical for trimer stability. Our approach provides a means to produce prefusion-closed Env trimers from diverse HIV-1 strains, a substantial advance for vaccine development.