CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5

Nature. 1996 Nov 14;384(6605):179-83. doi: 10.1038/384179a0.


For efficient entry into target cells, primary macrophage-tropic and laboratory-adapted human immunodeficiency viruses type 1 (HIV-1) require particular chemokine receptors, CCR-5 and CXCR-4, respectively, as well as the primary receptor CD4 (refs 1-6). Here we show that a complex of gp120, the exterior envelope glycoprotein, of macrophage-tropic primary HIV-1 and soluble CD4 interacts specifically with CCR-5 and inhibits the binding of the natural CCR-5 ligands, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta (refs 7, 8). The apparent affinity of the interaction between gp120 and CCR-5 was dramatically lower in the absence of soluble CD4. Additionally, in the absence of gp120, an interaction between a two-domain CD4 fragment and CCR-5 was observed. A gp120 fragment retaining the CD4-binding site and overlapping epitopes was able to interact with CCR-5 only if the V3 loop, which can specify HIV-1 tropism and chemokine receptor choice, was also present on the molecule. Neutralizing antibodies directed against either CD4-induced or V3 epitopes on gp120 blocked the interaction of gp12O-CD4 complexes with CCR-5. These results suggest that HIV-1 attachment to CD4 creates a high-affinity binding site for CCR-5, leading to membrane fusion and virus entry.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Binding Sites
  • Binding, Competitive
  • CD4 Antigens / metabolism*
  • Chemokine CCL3
  • Chemokine CCL4
  • Drosophila
  • HIV Antibodies / immunology
  • HIV Envelope Protein gp120 / immunology
  • HIV Envelope Protein gp120 / metabolism*
  • HIV-1 / metabolism*
  • Humans
  • Macrophage Inflammatory Proteins / metabolism
  • Membrane Fusion
  • Mice
  • Neutralization Tests
  • Peptide Fragments / metabolism
  • Receptors, CCR5
  • Receptors, Cytokine / metabolism*
  • Receptors, HIV / metabolism*
  • Recombinant Proteins / metabolism
  • Tumor Cells, Cultured


  • Antibodies, Monoclonal
  • CD4 Antigens
  • Chemokine CCL3
  • Chemokine CCL4
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • HIV envelope protein gp120 (305-321)
  • Macrophage Inflammatory Proteins
  • Peptide Fragments
  • Receptors, CCR5
  • Receptors, Cytokine
  • Receptors, HIV
  • Recombinant Proteins
  • recombinant soluble CD4