Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env. Academic Article uri icon

Overview

MeSH

  • Antigens, CD4
  • Crystallography, X-Ray
  • Epitopes
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Protein Conformation
  • Protein Multimerization
  • Virus Internalization

MeSH Major

  • Antibodies, Neutralizing
  • HIV Antibodies
  • HIV Infections
  • HIV-1
  • env Gene Products, Human Immunodeficiency Virus

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.

authors

publication date

  • July 2015

has subject area

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

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4706170

Digital Object Identifier (DOI)

  • 10.1038/nsmb.3051

PubMed ID

  • 26098315

Additional Document Info

start page

  • 522

end page

  • 531

volume

  • 22

number

  • 7