Interdomain Stabilization Impairs CD4 Binding and Improves Immunogenicity of the HIV-1 Envelope Trimer

P Zhang, J Gorman, H Geng, Q Liu, Y Lin, Y Tsybovsky, EP Go, B Dey, T Andine, A Kwon, M Patel, D Gururani, F Uddin, C Guzzo, R Cimbro, H Miao, K McKee, GY Chuang, L Martin, F SironiMS Malnati, H Desaire, EA Berger, JR Mascola, MA Dolan, PD Kwong, P Lusso

Research output: Contribution to journalArticle

Abstract

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. 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. © 2018
Original languageEnglish
Pages (from-to)832-844.e6
JournalCell Host and Microbe
Volume23
Issue number6
DOIs
Publication statusPublished - 2018

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HIV-1
Neutralizing Antibodies
Polysaccharides
HIV Envelope Protein gp160
Vaccines
Viruses
AIDS Vaccines
Crystallization
Disulfides
Immunization
Cell Membrane
Rabbits
Infection
Therapeutics

Cite this

Zhang, P., Gorman, J., Geng, H., Liu, Q., Lin, Y., Tsybovsky, Y., ... Lusso, P. (2018). Interdomain Stabilization Impairs CD4 Binding and Improves Immunogenicity of the HIV-1 Envelope Trimer. Cell Host and Microbe, 23(6), 832-844.e6. https://doi.org/10.1016/j.chom.2018.05.002

Interdomain Stabilization Impairs CD4 Binding and Improves Immunogenicity of the HIV-1 Envelope Trimer. / Zhang, P; Gorman, J; Geng, H; Liu, Q; Lin, Y; Tsybovsky, Y; Go, EP; Dey, B; Andine, T; Kwon, A; Patel, M; Gururani, D; Uddin, F; Guzzo, C; Cimbro, R; Miao, H; McKee, K; Chuang, GY; Martin, L; Sironi, F; Malnati, MS; Desaire, H; Berger, EA; Mascola, JR; Dolan, MA; Kwong, PD; Lusso, P.

In: Cell Host and Microbe, Vol. 23, No. 6, 2018, p. 832-844.e6.

Research output: Contribution to journalArticle

Zhang, P, Gorman, J, Geng, H, Liu, Q, Lin, Y, Tsybovsky, Y, Go, EP, Dey, B, Andine, T, Kwon, A, Patel, M, Gururani, D, Uddin, F, Guzzo, C, Cimbro, R, Miao, H, McKee, K, Chuang, GY, Martin, L, Sironi, F, Malnati, MS, Desaire, H, Berger, EA, Mascola, JR, Dolan, MA, Kwong, PD & Lusso, P 2018, 'Interdomain Stabilization Impairs CD4 Binding and Improves Immunogenicity of the HIV-1 Envelope Trimer', Cell Host and Microbe, vol. 23, no. 6, pp. 832-844.e6. https://doi.org/10.1016/j.chom.2018.05.002
Zhang, P ; Gorman, J ; Geng, H ; Liu, Q ; Lin, Y ; Tsybovsky, Y ; Go, EP ; Dey, B ; Andine, T ; Kwon, A ; Patel, M ; Gururani, D ; Uddin, F ; Guzzo, C ; Cimbro, R ; Miao, H ; McKee, K ; Chuang, GY ; Martin, L ; Sironi, F ; Malnati, MS ; Desaire, H ; Berger, EA ; Mascola, JR ; Dolan, MA ; Kwong, PD ; Lusso, P. / Interdomain Stabilization Impairs CD4 Binding and Improves Immunogenicity of the HIV-1 Envelope Trimer. In: Cell Host and Microbe. 2018 ; Vol. 23, No. 6. pp. 832-844.e6.
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