Uncleaved prefusion-optimized gp140 trimers derived from analysis of HIV-1 envelope metastability
Year: 2016
Type: article
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.
Source: Nature Communications
DOI: 10.1038/ncomms12040
Authors: Leopold Kong, Linling He, Natalia de Val, Nemil Vora, Charles D. Morris, Parisa Azadnia, Devin Sok, Bin Zhou, Dennis R. Burton, Andrew B. Ward, Ian A. Wilson, Jiang Zhu
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Energy, International AIDS Vaccine Initiative, National Institutes of Health, Office of Science, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Center for Research Resources, Basic Energy Sciences, Biological and Environmental Research, SLAC National Accelerator Laboratory
Awards: G102163711, G1066706594, G113944070, G1286251239, G1403976416, G1804828992, G1831385526, G1984473900, G2237160108, G2287611682, G2300450775, G262962599, G2857925935, G3488436650, G3629260272, G4047395780, G4068090750, G409777406, G426311843, G4269941704, G4280418065, G498139845, G5368254702, G5387317844, G5607048534, Cleaved, stabilized HIV-1 Env trimers for structural and vaccine studies, G6848031779, G6918803902, G7583137537, A Synchroton Radiation Structural Biology Resource, G8909705110, G9000028044, G9000069621, G9000075412, G9000140088, G9000235933, G9000260613, G9000331358, G9000350772, G969889393, G993149817
OpenAlex ID: W2465389976