Structure and Immune Recognition of Trimeric Pre-Fusion HIV-1 Env

Nature. 2014 Oct 23;514(7523):455-61. doi: 10.1038/nature13808. Epub 2014 Oct 8.

Abstract

The human immunodeficiency virus type 1 (HIV-1) envelope (Env) spike, comprising three gp120 and three gp41 subunits, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a post-fusion state. As the sole viral antigen on the HIV-1 virion surface, Env is both the target of neutralizing antibodies and a focus of vaccine efforts. Here we report the structure at 3.5 Å resolution for an HIV-1 Env trimer captured in a mature closed state by antibodies PGT122 and 35O22. This structure reveals the pre-fusion conformation of gp41, indicates rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition. Pre-fusion gp41 encircles amino- and carboxy-terminal strands of gp120 with four helices that form a membrane-proximal collar, fastened by insertion of a fusion peptide-proximal methionine into a gp41-tryptophan clasp. Spike rearrangements required for entry involve opening the clasp and expelling the termini. N-linked glycosylation and sequence-variable regions cover the pre-fusion closed spike; we used chronic cohorts to map the prevalence and location of effective HIV-1-neutralizing responses, which were distinguished by their recognition of N-linked glycan and tolerance for epitope-sequence variation.

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

  • AIDS Vaccines / chemistry
  • AIDS Vaccines / immunology
  • Amino Acid Sequence
  • Antibodies, Neutralizing / immunology
  • Cohort Studies
  • Crystallography, X-Ray
  • Genetic Variation
  • Glycosylation
  • HIV Antibodies / immunology
  • HIV Envelope Protein gp120 / chemistry*
  • HIV Envelope Protein gp120 / genetics
  • HIV Envelope Protein gp120 / immunology*
  • HIV Envelope Protein gp41 / chemistry*
  • HIV Envelope Protein gp41 / genetics
  • HIV Envelope Protein gp41 / immunology*
  • HIV Infections / immunology
  • Humans
  • Immune Evasion
  • Membrane Fusion
  • Models, Molecular
  • Molecular Sequence Data
  • Polysaccharides / chemistry
  • Polysaccharides / immunology
  • Protein Multimerization
  • Protein Structure, Quaternary
  • Protein Subunits / chemistry
  • Protein Subunits / genetics
  • Protein Subunits / immunology
  • Structural Homology, Protein
  • Virus Internalization

Substances

  • AIDS Vaccines
  • Antibodies, Neutralizing
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • HIV Envelope Protein gp41
  • Polysaccharides
  • Protein Subunits

Associated data

  • PDB/4TVP