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Sci Adv. 2018 Nov 21;4(11):eaau6769. doi: 10.1126/sciadv.aau6769. eCollection 2018 Nov.

HIV-1 vaccine design through minimizing envelope metastability.

Author information

1
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
2
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
3
International AIDS Vaccine Initiative Neutralizing Antibody Center and the Collaboration for AIDS Vaccine Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
4
Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
5
Centre for Biological Sciences and Institute for Life Sciences, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK.
6
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Cambridge, MA 02139-3583, USA.
7
Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.

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 (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.

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