The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/10/1383/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 8, October 20, 1997 1383-1388

Brief Definitive Reports

Inhibition of T-tropic HIV Strains by Selective Antagonization of the Chemokine Receptor CXCR4

Dominique Schols*, Sofie Struyf{ddagger}, Jo Van Damme{ddagger}, José A. Esté*, Geoffrey Henson§, and Erik De Clercq*

From the * Laboratory of Experimental Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium; {ddagger} Laboratory of Molecular Immunology, Rega Institute for Medical Research, B-3000 Leuven, Belgium; and § AnorMED, Langley, British Columbia, Canada, V2Y 1N5

Bicyclams are a novel class of antiviral compounds that are highly potent and selective inhibitors of the replication of HIV-1 and HIV-2. Surprisingly, however, when the prototype compound AMD3100 was tested against M-tropic virus strains such as BaL, ADA, JR-CSF, and SF-162 in human peripheral blood mononuclear cells, the compound was completely inactive. Because of the specific and potent inhibitory effect of AMD3100 on T-tropic viruses, but not M-tropic viruses, it was verified that AMD3100 interacts with the CXC-chemokine receptor CXCR4, the main coreceptor used by T-tropic viruses. AMD3100 dose dependently inhibited the binding of a specific CXCR4 monoclonal antibody to SUP-T1 cells as measured by flow cytometry. It did not inhibit the binding of the biotinylated CC-chemokine macrophage inflammatory protein (MIP) 1{alpha} or MIP-1β, ligands for the chemokine receptor CCR5 (the main coreceptor for M-tropic viruses). In addition, AMD3100 completely blocked (a) the Ca2+ flux at 100 ng/ml in lymphocytic SUP-T1 and monocytic THP-1 cells, and (b) the chemotactic responses of THP-1 cells induced by stromal cell–derived factor 1{alpha}, the natural ligand for CXCR4. Finally, AMD3100 had no effect on the Ca2+ flux induced by the CC-chemokines MIP-1{alpha}, regulated on activation normal T cell expressed and secreted (RANTES; also a ligand for CCR5), or monocyte chemoattractant protein 3 (a ligand for CCR1 and CCR2b), nor was it able to induce Ca2+ fluxes by itself. The bicyclams are, to our knowledge, the first low molecular weight anti-HIV agents shown to act as potent and selective CXCR4 antagonists.

Address correspondence to Dominique Schols, Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Phone: 32-16-33-73-41; Fax: 32-16-33-73-40; E-mail: dominique.schols{at}rega.kuleuven.ac.be


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