HIV-1 vaccine design through minimizing envelope metastability.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30474059.
- Also identified by DOI 10.1126/sciadv.aau6769 and PMC identifier 6248932.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sub>ECTO</sub>) is the main source of envelope metastability by replacing wild-type gp41<sub>ECTO</sub> with BG505 gp41<sub>ECTO</sub> of the uncleaved prefusion-optimized (UFO) design. These gp41<sub>ECTO</sub>-swapped trimers can be produced in CHO cells with high yield and high purity. The crystal structure of a gp41<sub>ECTO</sub>-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<sub>ECTO</sub> suggest an evolutionary root of metastability. The gp41<sub>ECTO</sub>-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.
Medical subject headings
- AIDS Vaccines
- Drug Design
- HIV Envelope Protein gp41
- HIV Infections
- HIV-1
- env Gene Products, Human Immunodeficiency Virus