J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/10/1395/06 $2.00
Volume 186, Number 8, October 20, 1997 1395-1400

BRIEF DEFINITIVE REPORT:
A Small-molecule Inhibitor Directed against the Chemokine Receptor CXCR4 Prevents its Use as an HIV-1 Coreceptor

By Benjamin J. Doranz,^* Kathie Grovit-Ferbas,^§ Matthew P. Sharron,^* Si-Hua Mao,^§ Matthew Bidwell Goetz,^§ Eric S. Daar,^§ Robert W. Doms,^* and William A. O'Brien^¶

From the ^* Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104;  Department of Medicine, West Los Angeles Veterans Affairs Medical Center, ^§ University of California at Los Angeles School of Medicine, and  Cedars-Sinai Medical Center, Los Angeles, California; and ^¶ Department of Medicine, University of Texas Medical Branch, Galveston, Texas

The chemokine receptor CXCR4 is the major coreceptor used for cellular entry by T cell- tropic human immunodeficiency virus (HIV)-1 strains, whereas CCR5 is used by macrophage (M)-tropic strains. Here we show that a small-molecule inhibitor, ALX40-4C, inhibits HIV-1 envelope (Env)-mediated membrane fusion and viral entry directly at the level of coreceptor use. ALX40-4C inhibited HIV-1 use of the coreceptor CXCR4 by T- and dual-tropic HIV-1 strains, whereas use of CCR5 by M- and dual-tropic strains was not inhibited. Dual-tropic viruses capable of using both CXCR4 and CCR5 were inhibited by ALX40-4C only when cells expressed CXCR4 alone. ALX40-4C blocked stromal-derived factor (SDF)-1-mediated activation of CXCR4 and binding of the monoclonal antibody 12G5 to cells expressing CXCR4. Overlap of the ALX40-4C binding site with that of 12G5 and SDF implicates direct blocking of Env interactions, rather than downregulation of receptor, as the mechanism of inhibition. Thus, ALX40-4C represents a small-molecule inhibitor of HIV-1 infection that acts directly against a chemokine receptor at the level of Env-mediated membrane fusion.

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