CCR5 Binds Multiple CC-Chemokines: MCP-3 Acts as a Natural Antagonist

• DOI: 10.1182/blood.v94.6.1899
• Publication Date: 2019-10-14T02:32:54Z
• Authors: Cédric Blanpain; Isabelle Migeotte; Benhur Lee; Jalal Vakili; Benjamin J. Doranz; Cédric Govaerts; Gilbert Vassart; Robert W. Doms; Marc Parmentier
• Keywords: CCR5 receptor antagonist; Macrophage inflammatory protein; Chemokine receptor CCR5

AbstractCCR5 was first characterized as a receptor for MIP-1, MIP-1β, 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 [125I]-MIP-1β 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-1β, MIP-1, and RANTES, five other CC-chemokines could compete for [125I]-MIP-1β binding: MCP-2, MCP-3, MCP-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 eliciting a functional response, MCP-3 could also inhibit the activation of CCR5 by MIP-1β 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-1β 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-1β. 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.