Structural basis of immune evasion at the site of CD4 attachment on HIV-1 gp120

Science. 2009 Nov 20;326(5956):1123-7. doi: 10.1126/science.1175868.

Abstract

The site on HIV-1 gp120 that binds to the CD4 receptor is vulnerable to antibodies. However, most antibodies that interact with this site cannot neutralize HIV-1. To understand the basis of this resistance, we determined co-crystal structures for two poorly neutralizing, CD4-binding site (CD4BS) antibodies, F105 and b13, in complexes with gp120. Both antibodies exhibited approach angles to gp120 similar to those of CD4 and a rare, broadly neutralizing CD4BS antibody, b12. Slight differences in recognition, however, resulted in substantial differences in F105- and b13-bound conformations relative to b12-bound gp120. Modeling and binding experiments revealed these conformations to be poorly compatible with the viral spike. This incompatibility, the consequence of slight differences in CD4BS recognition, renders HIV-1 resistant to all but the most accurately targeted antibodies.

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

  • Amino Acid Sequence
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Neutralizing / metabolism
  • Binding Sites
  • Binding Sites, Antibody
  • CD4 Antigens / chemistry
  • CD4 Antigens / metabolism*
  • Crystallography, X-Ray
  • Epitopes
  • HIV Antibodies / chemistry*
  • HIV Antibodies / immunology*
  • HIV Antibodies / metabolism
  • HIV Envelope Protein gp120 / chemistry*
  • HIV Envelope Protein gp120 / immunology*
  • HIV Envelope Protein gp120 / metabolism
  • HIV-1
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Immune Evasion*
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptide Fragments / immunology
  • Peptide Fragments / metabolism
  • Protein Conformation

Substances

  • Antibodies, Neutralizing
  • CD4 Antigens
  • Epitopes
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • HIV envelope protein gp120 (305-321)
  • Peptide Fragments
  • gp120 protein, Human immunodeficiency virus 1

Associated data

  • PDB/3HI1
  • PDB/3IDX
  • PDB/3IDY