A coherent HIV-1 vaccine strategy addresses envelope stabilization, nanoparticle display, antibody response, and manufacture. 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 gp41ECTO with BG505 gp41ECTO of 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 gp41ECTO suggest 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.
HIV-1 vaccine design through minimizing envelope metastability
Linling He,Sonu Kumar,Joel D. Allen,Deli Huang,Xiaohe Lin,Colin J. Mann,Karen L Saye-Francisco,Jeffrey Copps,A. Sarkar,Gabrielle S. Blizard,G. Ozorowski,D. Sok,M. Crispin,A. Ward,D. Nemazee,D. Burton,I. Wilson,Jiang Zhu
Published 2018 in Science Advances
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- Publication year
2018
- Venue
Science Advances
- Publication date
2018-07-04
- Fields of study
Biology, Medicine, Chemistry
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
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