Overview
Publication
Sci Adv. 2018 Nov; 4(11):eaau6769.
PubMed ID: 30474059
Title
HIV-1 vaccine design through minimizing envelope metastability
Authors
He L, Kumar S, Allen JD, Huang D, Lin X, Mann CJ, Saye-Francisco KL, Copps J, Sarkar A, Blizard GS, Ozorowski G, Sok D, Crispin M, Ward AB, Nemazee D, Burton DR, Wilson IA, Zhu J
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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