HIV-1 vaccine design through minimizing envelope metastability

Year

2018

Type(s)

Linling He, Sonu Kumar, Joel D. Allen, Deli Huang, Xiaohe Lin, Colin J. Mann, Karen L. Saye-Francisco, Jeffrey Copps, Anita Sarkar, Gabrielle S. Blizard, Gabriel Ozorowski, Devin Sok, Max Crispin, Andrew B. Ward, David Nemazee, Dennis R. Burton, Ian A. Wilson and Jiang Zhu

Source

Science Advances21 Nov 2018 : eaau6769

Url

http://advances.sciencemag.org/content/4/11/eaau6769

Bibtext

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_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.

Download Now