Uncleaved prefusion-optimized gp140 trimers derived from analysis of HIV-1 envelope metastability.

TitleUncleaved prefusion-optimized gp140 trimers derived from analysis of HIV-1 envelope metastability.
Publication TypeJournal Article
Year of Publication2016
AuthorsKong L, He L, de Val N, Vora N, Morris CD, Azadnia P, Sok D, Zhou B, Burton DR, Ward AB, Wilson IA, Zhu J
JournalNat Commun
Volume7
Pagination12040
Date Published06/28/2016
ISSN2041-1723
Abstract

The trimeric HIV-1 envelope glycoprotein (Env) is critical for host immune recognition and neutralization. Despite advances in trimer design, the roots of Env trimer metastability remain elusive. Here we investigate the contribution of two Env regions to metastability. First, we computationally redesign a largely disordered bend in heptad region 1 (HR1) of SOSIP trimers that connects the long, central HR1 helix to the fusion peptide, substantially improving the yield of soluble, well-folded trimers. Structural and antigenic analyses of two distinct HR1 redesigns confirm that redesigned Env closely mimics the native, prefusion trimer with a more stable gp41. Next, we replace the cleavage site between gp120 and gp41 with various linkers in the context of an HR1 redesign. Electron microscopy reveals a potential fusion intermediate state for uncleaved trimers containing short but not long linkers. Together, these results outline a general approach for stabilization of Env trimers from diverse HIV-1 strains.

DOI10.1038/ncomms12040
Alternate JournalNat Commun
PubMed ID27349805
Grant ListP01 AI110657 / AI / NIAID NIH HHS / United States
R56 AI084817 / AI / NIAID NIH HHS / United States
U54 GM094586 / GM / NIGMS NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
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