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Title: HIV-1 vaccine design through minimizing envelope metastability

Abstract

Overcoming envelope metastability is crucial to trimer-based HIV-1 vaccine design. Here, we present a coherent vaccine strategy by minimizing metastability. For 10 strains across five clades, we demonstrate that the gp41 ectodomain (gp41 ECTO) is the main source of envelope metastability by replacing wild-type gp41 ECTOwith BG505 gp41 ECTOof the uncleaved prefusion-optimized (UFO) design. These gp41 ECTO-swapped trimers can be produced in CHO cells with high yield and high purity. The crystal structure of a gp41 ECTO-swapped trimer elucidates how a neutralization-resistant tier 3 virus evades antibody recognition of the V2 apex. UFO trimers of transmitted/founder viruses and UFO trimers containing a consensus-based ancestral gp41 ECTOsuggest an evolutionary root of metastability. The gp41 ECTO-stabilized trimers can be readily displayed on 24- and 60-meric nanoparticles, with incorporation of additional T cell help illustrated for a hyperstable 60-mer, I3-01. In mice and rabbits, these gp140 nanoparticles induced tier 2 neutralizing antibody responses more effectively than soluble trimers.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NCINIGMS
OSTI Identifier:
1499778
Resource Type:
Journal Article
Journal Name:
Science Advances
Additional Journal Information:
Journal Volume: 4; Journal Issue: 11; Journal ID: ISSN 2375-2548
Publisher:
AAAS
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

He, Linling, Kumar, Sonu, Allen, Joel D., Huang, Deli, Lin, Xiaohe, Mann, Colin J., Saye-Francisco, Karen L., Copps, Jeffrey, Sarkar, Anita, Blizard, Gabrielle S., Ozorowski, Gabriel, Sok, Devin, Crispin, Max, Ward, Andrew B., Nemazee, David, Burton, Dennis R., Wilson, Ian A., and Zhu, Jiang. HIV-1 vaccine design through minimizing envelope metastability. United States: N. p., 2018. Web. doi:10.1126/sciadv.aau6769.
He, Linling, Kumar, Sonu, Allen, Joel D., Huang, Deli, Lin, Xiaohe, Mann, Colin J., Saye-Francisco, Karen L., Copps, Jeffrey, Sarkar, Anita, Blizard, Gabrielle S., Ozorowski, Gabriel, Sok, Devin, Crispin, Max, Ward, Andrew B., Nemazee, David, Burton, Dennis R., Wilson, Ian A., & Zhu, Jiang. HIV-1 vaccine design through minimizing envelope metastability. United States. doi:10.1126/sciadv.aau6769.
He, Linling, Kumar, Sonu, Allen, Joel D., Huang, Deli, Lin, Xiaohe, Mann, Colin J., Saye-Francisco, Karen L., Copps, Jeffrey, Sarkar, Anita, Blizard, Gabrielle S., Ozorowski, Gabriel, Sok, Devin, Crispin, Max, Ward, Andrew B., Nemazee, David, Burton, Dennis R., Wilson, Ian A., and Zhu, Jiang. Thu . "HIV-1 vaccine design through minimizing envelope metastability". United States. doi:10.1126/sciadv.aau6769.
@article{osti_1499778,
title = {HIV-1 vaccine design through minimizing envelope metastability},
author = {He, Linling and Kumar, Sonu and Allen, Joel D. and Huang, Deli and Lin, Xiaohe and Mann, Colin J. and Saye-Francisco, Karen L. and Copps, Jeffrey and Sarkar, Anita and Blizard, Gabrielle S. and Ozorowski, Gabriel and Sok, Devin and Crispin, Max and Ward, Andrew B. and Nemazee, David and Burton, Dennis R. and Wilson, Ian A. and Zhu, Jiang},
abstractNote = {Overcoming envelope metastability is crucial to trimer-based HIV-1 vaccine design. Here, we present a coherent vaccine strategy by minimizing metastability. For 10 strains across five clades, we demonstrate that the gp41 ectodomain (gp41ECTO) is the main source of envelope metastability by replacing wild-type gp41ECTOwith BG505 gp41ECTOof the uncleaved prefusion-optimized (UFO) design. These gp41ECTO-swapped trimers can be produced in CHO cells with high yield and high purity. The crystal structure of a gp41ECTO-swapped trimer elucidates how a neutralization-resistant tier 3 virus evades antibody recognition of the V2 apex. UFO trimers of transmitted/founder viruses and UFO trimers containing a consensus-based ancestral gp41ECTOsuggest an evolutionary root of metastability. The gp41ECTO-stabilized trimers can be readily displayed on 24- and 60-meric nanoparticles, with incorporation of additional T cell help illustrated for a hyperstable 60-mer, I3-01. In mice and rabbits, these gp140 nanoparticles induced tier 2 neutralizing antibody responses more effectively than soluble trimers.},
doi = {10.1126/sciadv.aau6769},
journal = {Science Advances},
issn = {2375-2548},
number = 11,
volume = 4,
place = {United States},
year = {2018},
month = {11}
}