Interdomain stabilization impairs CD4 binding and improves immunogenicity of the HIV-1 envelope trimer

Peng Zhang (1) , Jason Gorman (2) , Hui Geng (2) , Qingbo Liu (1) , Yin Lin (1) , Yaroslav Tsybovsky (3) , Eden Go (4) , Barna Dey (5) , Tsion Andine (1) , Alice Kwon (1) , Mit Patel (1) , Deepali Gururani (1) , Ferzan Uddin (1) , Christina Guzzo (1) , Raffaello Cimbro (1) , Huiyi Miao (1) , Krisha Mckee (2) , Gwo-Yu Chuang (2) , Loïc M Martin (6, 7, 8) , Francesca Sironi (9) , Mauro S. Malnati (9) , Heather Desaire (4) , Edward A. Berger (5) , John R. Mascola (2) , Michael A. Dolan (5) , Peter D. Kwong (2) , Paolo Lusso (1)

1 Laboratory of Immunoregulation [Bethesda, MD, USA]
2 VRC - Vaccine Research Center
3 FNLCR - Frederick National Laboratory for Cancer Research
4 KU - University of Kansas [Lawrence]
5 NIAID-NIH - National Institute of Allergy and Infectious Diseases [Bethesda]
6 JOLIOT - Institut des Sciences du Vivant Frédéric JOLIOT
7 SIMoS - Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO)
8 MTS - Médicaments et Technologies pour la Santé
9 San Raffaele Scientific Institute

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.

Domaines: Chimie thérapeutique; Biochimie [q-bio.BM]; Immunothérapie; Vaccinologie; Virologie

Peng Zhang, Jason Gorman, Hui Geng, Qingbo Liu, Yin Lin, et al.. Interdomain stabilization impairs CD4 binding and improves immunogenicity of the HIV-1 envelope trimer. Cell Host and Microbe, 2018, 23 (6), pp.832-844.e6. ⟨10.1016/j.chom.2018.05.002⟩. ⟨hal-02531048⟩