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Nat Commun. 2016 Jun 28;7:12040. doi: 10.1038/ncomms12040.

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

Kong L1,2,3, He L4, de Val N1,2,3, Vora N4, Morris CD4, Azadnia P4, Sok D2,3,4, Zhou B5, Burton DR2,3,4,6, Ward AB1,2,3, Wilson IA1,2,3,7,8, Zhu J1,3,4.

Author information

1
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
2
International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
3
Scripps Center for HIV/AIDS Vaccine Immunology &Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA.
4
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
5
Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA.
6
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02139-3583, USA.
7
The Joint Center for Structural Genomics, The Scripps Research Institute, La Jolla, California 92037, USA.
8
Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.

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.

PMID:
27349805
PMCID:
PMC4931249
DOI:
10.1038/ncomms12040
[Indexed for MEDLINE]
Free PMC Article

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