Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env

Nat Struct Mol Biol. 2015 Jul;22(7):522-31. doi: 10.1038/nsmb.3051. Epub 2015 Jun 22.

Abstract

As the sole viral antigen on the HIV-1-virion surface, trimeric Env is a focus of vaccine efforts. Here we present the structure of the ligand-free HIV-1-Env trimer, fix its conformation and determine its receptor interactions. Epitope analyses revealed trimeric ligand-free Env to be structurally compatible with broadly neutralizing antibodies but not poorly neutralizing ones. We coupled these compatibility considerations with binding antigenicity to engineer conformationally fixed Envs, including a 201C 433C (DS) variant specifically recognized by broadly neutralizing antibodies. DS-Env retained nanomolar affinity for the CD4 receptor, with which it formed an asymmetric intermediate: a closed trimer bound by a single CD4 without the typical antigenic hallmarks of CD4 induction. Antigenicity-guided structural design can thus be used both to delineate mechanism and to fix conformation, with DS-Env trimers in virus-like-particle and soluble formats providing a new generation of vaccine antigens.

Publication types

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

MeSH terms

  • Antibodies, Neutralizing / immunology*
  • CD4 Antigens / immunology
  • Crystallography, X-Ray
  • Epitopes / immunology
  • HEK293 Cells
  • HIV Antibodies / immunology*
  • HIV Infections / immunology*
  • HIV Infections / virology
  • HIV-1 / chemistry
  • HIV-1 / immunology
  • HIV-1 / physiology*
  • Humans
  • Models, Molecular
  • Protein Conformation
  • Protein Multimerization
  • Virus Internalization
  • env Gene Products, Human Immunodeficiency Virus / chemistry*
  • env Gene Products, Human Immunodeficiency Virus / immunology*

Substances

  • Antibodies, Neutralizing
  • CD4 Antigens
  • Epitopes
  • HIV Antibodies
  • env Gene Products, Human Immunodeficiency Virus

Associated data

  • PDB/4ZMJ