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

Cell Host Microbe. 2018 Jun 13;23(6):832-844.e6. doi: 10.1016/j.chom.2018.05.002.

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.

Keywords: HIV-1; conformational changes; immunogenicity; neutralizing antibodies; pre-clinical models; protein stabilization; protein structure; receptor binding; vaccine; viral envelope.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIDS Vaccines / immunology
  • Animals
  • Antibodies, Neutralizing / immunology
  • CD4 Antigens / immunology*
  • CD4 Antigens / metabolism*
  • Female
  • HEK293 Cells
  • HIV Antibodies / immunology
  • HIV Antigens / chemistry
  • HIV Antigens / immunology
  • HIV Envelope Protein gp120 / chemistry
  • HIV Envelope Protein gp120 / genetics
  • HIV Envelope Protein gp120 / immunology
  • HIV Envelope Protein gp120 / metabolism
  • HIV Envelope Protein gp160 / chemistry
  • HIV Envelope Protein gp160 / immunology
  • HIV Envelope Protein gp160 / metabolism
  • HIV-1 / genetics
  • HIV-1 / immunology*
  • HIV-1 / pathogenicity
  • Humans
  • Immunization
  • Models, Molecular
  • Protein Binding / immunology*
  • Protein Conformation
  • Protein Domains* / immunology
  • Protein Stability*
  • Rabbits
  • Virus Internalization
  • env Gene Products, Human Immunodeficiency Virus / chemistry*
  • env Gene Products, Human Immunodeficiency Virus / genetics
  • env Gene Products, Human Immunodeficiency Virus / immunology*

Substances

  • AIDS Vaccines
  • Antibodies, Neutralizing
  • CD4 Antigens
  • HIV Antibodies
  • HIV Antigens
  • HIV Envelope Protein gp120
  • HIV Envelope Protein gp160
  • env Gene Products, Human Immunodeficiency Virus