CCR5 binds multiple CC-chemokines: MCP-3 acts as a natural antagonist

Blood. 1999 Sep 15;94(6):1899-905.


CCR5 was first characterized as a receptor for MIP-1alpha, MIP-1beta, and RANTES, and was rapidly shown to be the main coreceptor for M-tropic human immunodeficiency virus (HIV)-1 strains and simian immunodeficiency virus (SIV). Chemokines constitute a rapidly growing family of proteins and receptor-chemokine interactions are known to be promiscuous and redundant. We have therefore tested whether other CC-chemokines could bind to and activate CCR5. All CC-chemokines currently available were tested for their ability to compete with [(125)I]-MIP-1beta binding on a stable cell line expressing recombinant CCR5, and/or to induce a functional response in these cells. We found that in addition to MIP-1beta, MIP-1alpha, and RANTES, five other CC-chemokines could compete for [(125)I]-MIP-1beta binding: MCP-2, MCP-3, MCP-4, MCP-1, and eotaxin binding was characterized by IC(50) values of 0.22, 2.14, 5.89, 29.9, and 21.7 nmol/L, respectively. Among these ligands, MCP-3 had the remarkable property of binding CCR5 with high affinity without eliciting a functional response, MCP-3 could also inhibit the activation of CCR5 by MIP-1beta and may therefore be considered as a natural antagonist for CCR5. It was unable to induce significant endocytosis of the receptor. Chemokines that could compete with high affinity for MIP-1beta binding could also compete for monomeric gp120 binding, although with variable potencies; maximal gp120 binding inhibition was 80% for MCP-2, but only 30% for MIP-1beta. MCP-3 could compete efficiently for gp120 binding but was, however, found to be a weak inhibitor of HIV infection, probably as a consequence of its inability to downregulate the receptor.

Publication types

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

MeSH terms

  • Animals
  • Binding, Competitive
  • CCR5 Receptor Antagonists
  • CHO Cells
  • Cell Line
  • Chemokine CCL3
  • Chemokine CCL4
  • Chemokine CCL7
  • Chemokines, CC / metabolism*
  • Chemokines, CC / pharmacology
  • Cricetinae
  • Cytokines*
  • HIV Envelope Protein gp120 / metabolism
  • Humans
  • Kinetics
  • Macrophage Inflammatory Proteins / metabolism*
  • Monocyte Chemoattractant Proteins / pharmacology*
  • Receptors, CCR5 / immunology
  • Receptors, CCR5 / metabolism*
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Transfection


  • CCL7 protein, human
  • CCR5 Receptor Antagonists
  • Chemokine CCL3
  • Chemokine CCL4
  • Chemokine CCL7
  • Chemokines, CC
  • Cytokines
  • HIV Envelope Protein gp120
  • Macrophage Inflammatory Proteins
  • Monocyte Chemoattractant Proteins
  • Receptors, CCR5
  • Recombinant Proteins