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)-1α–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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20 October 1997
Brief Definitive Report|
October 20 1997
A Small-molecule Inhibitor Directed against the Chemokine Receptor CXCR4 Prevents its Use as an HIV-1 Coreceptor
Benjamin J. Doranz,
Benjamin J. Doranz
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
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Kathie Grovit-Ferbas,
Kathie Grovit-Ferbas
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
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Matthew P. Sharron,
Matthew P. Sharron
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
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Si-Hua Mao,
Si-Hua Mao
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
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Matthew Bidwell Goetz,
Matthew Bidwell Goetz
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
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Eric S. Daar,
Eric S. Daar
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
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Robert W. Doms,
Robert W. Doms
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
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William A. O'Brien
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
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Benjamin J. Doranz
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
Kathie Grovit-Ferbas
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
Matthew P. Sharron
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
Si-Hua Mao
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
Matthew Bidwell Goetz
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
Eric S. Daar
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
Robert W. Doms
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
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
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: [email protected]; 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: [email protected]
Received:
July 03 1997
Revision Received:
August 05 1997
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1997
J Exp Med (1997) 186 (8): 1395–1400.
Article history
Received:
July 03 1997
Revision Received:
August 05 1997
Citation
Benjamin J. Doranz, Kathie Grovit-Ferbas, Matthew P. Sharron, Si-Hua Mao, Matthew Bidwell Goetz, Eric S. Daar, Robert W. Doms, William A. O'Brien; A Small-molecule Inhibitor Directed against the Chemokine Receptor CXCR4 Prevents its Use as an HIV-1 Coreceptor . J Exp Med 20 October 1997; 186 (8): 1395–1400. doi: https://doi.org/10.1084/jem.186.8.1395
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