MOLECULAR-CLONING AND FUNCTIONAL-CHARACTERIZATION OF A NOVEL HUMAN CCCHEMOKINE RECEPTOR (CCR5) FOR RANTES, MIP-1-BETA, AND MIP-1-ALPHA

Chemokines affect leukocyte chemotactic and activation activities thro ugh specific G protein-coupled receptors. In an effort to map the clos ely linked CC chemokine receptor genes, we identified a novel chemokin e receptor encoded 18 kilobase pairs downstream of the monocyte chemoa ttractant protein-1 (MCP-1) receptor (CCR2) gene on human chromosome 3 p21. The deduced amino acid sequence of this novel receptor, designate d CCR5, is most similar to CCR2B, sharing 71% identical residues. Tran sfected cells expressing the receptor bind RANTES (regulated on activa tion normal T cell expressed), MLP-1 beta, and MLP-1 alpha, with high affinity and generate inositol phosphates in response to these chemoki nes. This same combination of chemokines has recently been shown to po tently inhibit human immunodeficiency virus replication in human perip heral blood leukocytes (Cocchi, F., DeVico, A. L., Garzino-Demo, A., A rya, S. K., Gallo, R. C., and Lusso, P. (1995) Science 270, 1811-1815) . CCR5 is expressed in lymphoid organs such as thymus and spleen, as w ell as in peripheral blood leukocytes, including macrophages and T cel ls, and is the first example of a human chemokine receptor that signal s in response to MIP-1 beta.