The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/10/1395/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 8, October 20, 1997 1395-1400

Brief Definitive Reports

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

Benjamin J. Doranz*, Kathie Grovit-Ferbas{ddagger},§, Matthew P. Sharron*, Si-Hua Mao{ddagger},§, Matthew Bidwell Goetz{ddagger},§, 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; {ddagger} 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{alpha}–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.

Address correspondence to William A. O'Brien, Infectious Diseases, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0835. Phone: 409-747-2361; FAX: 409-747-0507; E-mail: wobrien{at}impol.utmb.edu; or address correspondence to Robert W. Doms, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104. Phone: 1-215-898-0890; FAX: 1-215-573-2883; E-mail: doms{at}mail.med.upenn.edu


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