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 journalArticlepeer-review


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
Issue number6
Publication statusPublished - 2018


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