HIV-1 vaccine design through minimizing envelope metastability

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

doi:10.1126/sciadv.aau6769

Title: HIV-1 vaccine design through minimizing envelope metastability

Journal Article · Fri Nov 02 00:00:00 EDT 2018 · Science Advances

DOI:https://doi.org/10.1126/sciadv.aau6769· OSTI ID:1499778

^[1]; Kumar, Sonu ^[1];

^[2]; Huang, Deli ^[1]; Lin, Xiaohe ^[1];

^[1]; Saye-Francisco, Karen L. ^[1];

^[1]; Sarkar, Anita ^[1]; Blizard, Gabrielle S. ^[1]; Ozorowski, Gabriel ^[1];

^[1];

^[2];

^[1];

^[3];

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^[1]

The Scripps Research Inst., La Jolla, CA (United States)
Univ. of Southampton (United Kingdom)
The Scripps Research Inst., La Jolla, CA (United States); Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States). Massachusetts General Hospital, Ragon Inst.

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_ECTO with BG505 gp41_ECTO of 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_ECTO suggest 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Cancer Institute (NCI); National Institute of General Medical Sciences (NIGMS); USDOE Office of Science (SC); International AIDS Vaccine Initiative Neutralizing Antibody Center; Bill & Melinda Gates Foundation; Collaboration for AIDS Vaccine Discovery; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery

Grant/Contract Number:: AC02-06CH11357; OPP1084519; OPP1115782; CHAVI-ID UM1 AI100663; AI084817; AI129698; AI125078-01A1

OSTI ID:: 1499778

Journal Information:: Science Advances, Vol. 4, Issue 11; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 45 works

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Stabilized diverse HIV-1 envelope trimers for vaccine design Wang, Qian; Ma, Bingting; Liang, Qingtai Emerging Microbes & Infections, Vol. 9, Issue 1 https://doi.org/10.1080/22221751.2020.1745093	journal	January 2020
HIV-1 Envelope Glycan Composition as a Key Determinant of Efficient Virus Transmission via DC-SIGN and Resistance to Inhibitory Lectins Jan, Muzafar; Upadhyay, Chitra; Hioe, Catarina E. iScience, Vol. 21 https://doi.org/10.1016/j.isci.2019.10.030	journal	November 2019

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