National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
AI084794, AI089618, AI106488, AI112489, AI100645
United States
Howard Hughes Medical Institute (HHMI)
United States
Bill & Melinda Gates Foundation
OPP1040741
United States
Citation
Journal: J Virol / Year: 2017 Title: Conformational States of a Soluble, Uncleaved HIV-1 Envelope Trimer. Authors: Yuhang Liu / Junhua Pan / Yongfei Cai / Nikolaus Grigorieff / Stephen C Harrison / Bing Chen / Abstract: The HIV-1 envelope spike [Env; trimeric (gp160) cleaved to (gp120/gp41)] induces membrane fusion, leading to viral entry. It is also the viral component targeted by neutralizing antibodies. Vaccine ...The HIV-1 envelope spike [Env; trimeric (gp160) cleaved to (gp120/gp41)] induces membrane fusion, leading to viral entry. It is also the viral component targeted by neutralizing antibodies. Vaccine development requires production, in quantities suitable for clinical studies, of a recombinant form that resembles functional Env. HIV-1 gp140 trimers-the uncleaved ectodomains of (gp160)-from a few selected viral isolates adopt a compact conformation with many antigenic properties of native Env spikes. One is currently being evaluated in a clinical trial. We report here low-resolution (20 Å) electron cryomicroscopy (cryoEM) structures of this gp140 trimer, which adopts two principal conformations, one closed and the other slightly open. The former is indistinguishable at this resolution from those adopted by a stabilized, cleaved trimer (SOSIP) or by a membrane-bound Env trimer with a truncated cytoplasmic tail (EnvΔCT). The latter conformation is closer to a partially open Env trimer than to the fully open conformation induced by CD4. These results show that a stable, uncleaved HIV-1 gp140 trimer has a compact structure close to that of native Env. Development of any HIV vaccine with a protein component (for either priming or boosting) requires production of a recombinant form to mimic the trimeric, functional HIV-1 envelope spike in quantities suitable for clinical studies. Our understanding of the envelope structure has depended in part on a cleaved, soluble trimer, known as SOSIP.664, stabilized by several modifications, including an engineered disulfide. This construct, which is difficult to produce in large quantities, has yet to induce better antibody responses than those to other envelope-based immunogens, even in animal models. The uncleaved ectodomain of the envelope protein, called gp140, has also been made as a soluble form to mimic the native Env present on the virion surface. Most HIV-1 gp140 preparations are not stable, however, and have an inhomogeneous conformation. The results presented here show that gp140 preparations from suitable isolates can adopt a compact, native-like structure, supporting its use as a vaccine candidate.
History
Deposition
Feb 28, 2017
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Header (metadata) release
Mar 8, 2017
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Map release
Mar 8, 2017
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Update
Dec 11, 2019
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Current status
Dec 11, 2019
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Digitization - Dimensions - Width: 3838 pixel / Digitization - Dimensions - Height: 3710 pixel / Digitization - Sampling interval: 5.0 µm / Number grids imaged: 1 / Number real images: 3138 / Average exposure time: 8.0 sec. / Average electron dose: 40.0 e/Å2 / Details: movies were collected in super resolution mode
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron optics
C2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.0 mm
Sample stage
Specimen holder model: OTHER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Tecnai Polara / Image courtesy: FEI Company
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Image processing
CTF correction
Software - Name: CTFFIND3
Startup model
Type of model: OTHER / Details: rosette method described in the paper
Final reconstruction
Applied symmetry - Point group: C3 (3 fold cyclic) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 21.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: FREALIGN (ver. 9.11) / Number images used: 17000
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