CCR5 binds multiple CC-chemokines: MCP-3 acts as a natural antagonist.
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.
Blanpain
C
C
IRIBHN and Service de Génétique Médicale, Université Libre de Bruxelles, Campus Erasme, Bruxelles, Belgium.
Migeotte
I
I
Lee
B
B
Vakili
J
J
Doranz
B J
BJ
Govaerts
C
C
Vassart
G
G
Doms
R W
RW
Parmentier
M
M
D000818:Animals; D001667:Binding, Competitive; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D002460:Cell Line; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054410:Chemokine CCL7; D019742:Chemokines, CC / Q000378:metabolism* / Q000494:pharmacology; D006224:Cricetinae; D016207:Cytokines; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism*; D018945:Monocyte Chemoattractant Proteins / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection
C515450:CCL7 protein, human; D065100:CCR5 Receptor Antagonists; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054410:Chemokine CCL7; D019742:Chemokines, CC; D016207:Cytokines; D015699:HIV Envelope Protein gp120; D019402:Macrophage Inflammatory Proteins; D018945:Monocyte Chemoattractant Proteins; D019713:Receptors, CCR5; D011994:Recombinant Proteins