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Zhang, Peng; Gorman, Jason; Geng, Hui; Liu, Qingbo; Lin, Yin; Tsybovsky, Yaroslav; Go, Eden P.; Dey, Barna; Andine, Tsion; Kwon, Alice; Patel, Mit; Gururani, Deepali; Uddin, Ferzan; Guzzo, Christina; Cimbro, Raffaello; Miao, Huiyi; McKee, Krisha; Chuang, Gwo-Yu; Martin, Loïc; Sironi, Francesca; Malnati, Mauro S.; Desaire, Heather; Berger, Edward A.; Mascola, John R.; Dolan, Michael A.; Kwong, Peter D.; Lusso, Paolo
Cell host & microbe, 06/2018, Letnik: 23, Številka: 6Journal Article
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. Display omitted •Interdomain locks stabilize soluble and membrane-bound HIV-1 Env trimers•Locked trimers maintain a native-like antigenicity but do not bind CD4•Locked trimers are resistant to CD4-induced disruption of immunogenicity•Immunized rabbits neutralized glycan-repaired autologous tier-2 viruses Binding to CD4 compromises the native antigenic state of the HIV-1 envelope trimer. Zhang et al. rationally designed interdomain-locked trimers that elicited the production of tier-2 neutralizing antibodies against glycan-repaired virus and were resistant to CD4-induced disruption of immunogenicity. This strategy provides a widely applicable template for HIV-1 Env-based vaccines.
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