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

CCR5 was first characterized as a receptor for MIP-1 alpha, MIP-1 beta, 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 recept or-chemokine interactions are known to be promiscuous and redundant. We hav e therefore tested whether other CC-chemokines could bind to and activate C CR5. All CC-chemokines currently available were tested for their ability to compete with [I-125]-MIP-1 beta binding on a stable cell line expressing r ecombinant CCR5, and/or to induce a functional response in these cells. We found that in addition to MIP-1 beta, MIP-1 alpha, and RANTES, five other C C-chemokines could compete for [I-125]-MIP-1 beta binding: MCP-2, MCP-3, MC P-4, MCP-1, and eotaxin binding was characterized by IC50 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 elic iting a functional response, MCP-3 could also inhibit the activation of CCR 5 by MIP-1 beta and may therefore be considered as a natural antagonist for CCR5. It was unable to induce significant endocytosis of the receptor. Che mokines that could compete with high affinity for MIP-1 beta 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-1 beta. 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. (C) 1999 by The American Socie ty of Hematology.