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

Kong, Leopold; He, Linling; de Val, Natalia; Vora, Nemil; Morris, Charles D.; Azadnia, Parisa; Sok, Devin; Zhou, Bin; Burton, Dennis R.; Ward, Andrew B.; Wilson, Ian A.; Zhu, Jiang

doi:10.1038/ncomms12040

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

Journal Article · Tue Jun 28 00:00:00 EDT 2016 · Nature Communications

DOI:https://doi.org/10.1038/ncomms12040· OSTI ID:1259891

Kong, Leopold ^[1]; He, Linling ^[1]; de Val, Natalia ^[1];

^[1]; Morris, Charles D. ^[1]; Azadnia, Parisa ^[1]; Sok, Devin ^[1]; Zhou, Bin ^[1]; Burton, Dennis R. ^[2]; Ward, Andrew B. ^[1]; Wilson, Ian A. ^[1]; Zhu, Jiang ^[1]

The Scripps Research Inst., La Jolla, CA (United States)
The Scripps Research Inst., La Jolla, CA (United States); Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); National Inst. of General Medical Sciences; National Center for Research Resouces

Grant/Contract Number:: AC02-06CH11357; P41GM103393; P41RR001209; U54 GM094586; AI084817

OSTI ID:: 1259891

Journal Information:: Nature Communications, Vol. 7, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 84 works

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