CD4-dependent, Antibody-Sensitive Interactions Between HIV-1 and Its Co-Receptor CCR-5

Nature. 1996 Nov 14;384(6605):184-7. doi: 10.1038/384184a0.

Abstract

The beta-chemokine receptor CCR-5 is an essential co-factor for fusion of HIV-1 strains of the non-syncytium-inducing (NSI) phenotype with CD4+ T-cells. The primary binding site for human immunodeficiency virus (HIV)-1 is the CD4 molecule, and the interaction is mediated by the viral surface glycoprotein gp120 (refs 6, 7). The mechanism of CCR-5 function during HIV-1 entry has not been defined, but we have shown previously that its beta-chemokine ligands prevent HIV-1 from fusing with the cell. We therefore investigated whether CCR-5 acts as a second binding site for HIV-1 simultaneously with or subsequent to the interaction between gp120 and CD4. We used a competition assay based on gp120 inhibition of the binding of the CCR-5 ligand, macrophage inflammatory protein (MIP)-1beta, to its receptor on activated CD4+ T cells or CCR-5-positive CD4- cells. We conclude that CD4 binding, although not absolutely necessary for the gp120-CCR-5 interaction, greatly increases its efficiency. Neutralizing monoclonal antibodies against several sites on gp120, including the V3 loop and CD4-induced epitopes, inhibited the interaction of gp120 with CCR-5, without affecting gp120-CD4 binding. Interference with HIV-1 binding to one or both of its receptors (CD4 and CCR-5) may be an important mechanism of virus neutralization.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Antibodies, Monoclonal / immunology
  • Binding, Competitive
  • CD4 Antigens / metabolism*
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Line
  • Cells, Cultured
  • Chemokine CCL4
  • HIV Antibodies / immunology
  • HIV Envelope Protein gp120 / immunology
  • HIV Envelope Protein gp120 / metabolism
  • HIV-1 / metabolism*
  • Humans
  • Macrophage Inflammatory Proteins / metabolism
  • Molecular Sequence Data
  • Neutralization Tests
  • Peptide Fragments / immunology
  • Peptide Fragments / metabolism
  • Protein Conformation
  • Receptors, CCR5
  • Receptors, Cytokine / metabolism*
  • Receptors, HIV / metabolism*
  • Recombinant Proteins / metabolism

Substances

  • Antibodies, Monoclonal
  • CD4 Antigens
  • 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