Interdomain stabilization impairs CD4 binding and improves immunogenicity of the HIV-1 envelope trimer
Résumé
The HIV-1 envelope (Env) spike is a trimer of gp120/gp41 heterodimers that mediates viral entry.
Binding to CD4 on the host cell membrane is the first essential step for infection but disrupts the
native antigenic state of Env, posing a key obstacle to vaccine development. We locked the HIV-1
Env trimer in a pre-fusion configuration, resulting in impaired CD4 binding and enhanced binding
to broadly neutralizing antibodies. This design was achieved via structure-guided introduction of
neo-disulfide bonds bridging the gp120 inner and outer domains and was successfully applied to
soluble trimers and native gp160 from different HIV-1 clades. Crystallization illustrated the
structural basis for CD4-binding impairment. Immunization of rabbits with locked trimers from
two different clades elicited neutralizing antibodies against tier-2 viruses with a repaired glycan
shield regardless of treatment with a functional CD4 mimic. Thus, interdomain stabilization
provides a widely applicable template for the design of Env-based HIV-1 vaccines.
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