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J Biol Chem, Vol. 273, Issue 8, 4289-4292, February 20, 1998

COMMUNICATION
Monocyte Chemotactic Protein-2 Activates CCR5 and Blocks CD4/CCR5-mediated HIV-1 Entry/Replication

Wanghua Gong, O. M. Zack Howard, Jim A. Turpin, Michael C. Grimm^§, Hirotsugu Ueda^§, Patrick W. Gray^¶, Carol J. Raport^¶, Joost J. Oppenheim^§, and Ji Ming Wang^§

From the Intramural Research Support Program and the  Developmental Therapeutics Program, SAIC Frederick and the ^§ Laboratory of Molecular Immunoregulation, Division of Basic Sciences, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 21702 and ^¶ ICOS Corporation, Bothell, Washington 98021

Human immunodeficiency virus, type I (HIV-1) cell-type tropism is dictated by chemokine receptor usage: T-cell line tropic viruses use CXCR4, whereas monocyte tropic viruses primarily use CCR5 as fusion coreceptors. CC chemokines macrophage inflammatory protein (MIP)-1, MIP-1, and RANTES (regulated on activation normal T cell expressed and secreted) inhibit CD4/CCR5-mediated HIV-1 cell fusion. MCP-2 is also a member of the CC chemokine subfamily and has the capacity to interact with at least two receptors including CCR-1 and CCR2B. In an effort to further characterize the binding properties of MCP-2 on leukocytes, we observed that MCP-2, but not MCP-1, effectively competed with MIP-1 for binding to monocytes, suggesting that MCP-2 may interact with CCR5. As predicted, MCP-2 competitively inhibited MIP-1 binding to HEK293 cells stably transfected with CCR5 (CCR5/293 cells). MCP-2 also bound to and induced chemotaxis of CCR5/293 cells with a potency comparable with that of MIP-1. Confocal microscopy indicates that MCP-2 caused remarkable and dose-dependent internalization of CCR5 in CCR5/293 cells. Furthermore, MCP-2 inhibited the entry/replication of HIV-1ADA in CCR5/293 cells coexpressing CD4. These results indicated that MCP-2 uses CCR5 as one of its functional receptors and is an additional potent natural inhibitor of HIV-1.

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Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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