J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/10/1383/06 $2.00
Volume 186, Number 8, October 20, 1997 1383-1388

BRIEF DEFINITIVE REPORT:
Inhibition of T-tropic HIV Strains by Selective Antagonization of the Chemokine Receptor CXCR4

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

From the ^* Laboratory of Experimental Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium;  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 or MIP-1, 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, the natural ligand for CXCR4. Finally, AMD3100 had no effect on the Ca²⁺ flux induced by the CC-chemokines MIP-1, 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.

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• Pluymers, W., Neamati, N., Pannecouque, C., Fikkert, V., Marchand, C., Burke, T. R. Jr., Pommier, Y., Schols, D., De Clercq, E., Debyser, Z., Witvrouw, M. (2000). Viral Entry as the Primary Target for the Anti-HIV Activity of Chicoric Acid and Its Tetra-Acetyl Esters. Mol. Pharmacol. 58: 641-648 [Abstract] [Full Text]  
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• Sharron, M., Pohlmann, S., Price, K., Lolis, E., Tsang, M., Kirchhoff, F., Doms, R. W., Lee, B. (2000). Expression and coreceptor activity of STRL33/Bonzo on primary peripheral blood lymphocytes. Blood 96: 41-49 [Abstract] [Full Text]  
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• Hendrix, C. W., Flexner, C., MacFarland, R. T., Giandomenico, C., Fuchs, E. J., Redpath, E., Bridger, G., Henson, G. W. (2000). Pharmacokinetics and Safety of AMD-3100, a Novel Antagonist of the CXCR-4 Chemokine Receptor, in Human Volunteers. Antimicrob. Agents Chemother. 44: 1667-1673 [Abstract] [Full Text]  
• De Clercq, E. (2000). Inhibition of HIV Infection by Bicyclams, Highly Potent and Specific CXCR4 Antagonists. Mol. Pharmacol. 57: 833-839 [Abstract] [Full Text]  
• Murphy, P. M., Baggiolini, M., Charo, I. F., Hebert, C. A., Horuk, R., Matsushima, K., Miller, L. H., Oppenheim, J. J., Power, C. A. (2000). International Union of Pharmacology. XXII. Nomenclature for Chemokine Receptors. Pharmacol. Rev. 52: 145-176 [Abstract] [Full Text]  
• Zhang, Y., Hatse, S., De Clercq, E., Schols, D. (2000). CXC-Chemokine Receptor 4 Is Not a Coreceptor for Human Herpesvirus 7 Entry into CD4+ T Cells. J. Virol. 74: 2011-2016 [Abstract] [Full Text]  
• Stine, J. T., Wood, C., Hill, M., Epp, A., Raport, C. J., Schweickart, V. L., Endo, Y., Sasaki, T., Simmons, G., Boshoff, C., Clapham, P., Chang, Y., Moore, P., Gray, P. W., Chantry, D. (2000). KSHV-encoded CC chemokine vMIP-III is a CCR4 agonist, stimulates angiogenesis, and selectively chemoattracts TH2 cells. Blood 95: 1151-1157 [Abstract] [Full Text]  
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• Trkola, A., Matthews, J., Gordon, C., Ketas, T., Moore, J. P. (1999). A Cell Line-Based Neutralization Assay for Primary Human Immunodeficiency Virus Type 1 Isolates That Use either the CCR5 or the CXCR4 Coreceptor. J. Virol. 73: 8966-8974 [Abstract] [Full Text]  
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• Murakami, T., Zhang, T.-Y., Koyanagi, Y., Tanaka, Y., Kim, J., Suzuki, Y., Minoguchi, S., Tamamura, H., Waki, M., Matsumoto, A., Fujii, N., Shida, H., Hoxie, J. A., Peiper, S. C., Yamamoto, N. (1999). Inhibitory Mechanism of the CXCR4 Antagonist T22 against Human Immunodeficiency Virus Type 1 Infection. J. Virol. 73: 7489-7496 [Abstract] [Full Text]  
• Reeves, J. D., Hibbitts, S., Simmons, G., McKnight, A., Azevedo-Pereira, J. M., Moniz-Pereira, J., Clapham, P. R. (1999). Primary Human Immunodeficiency Virus Type 2 (HIV-2) Isolates Infect CD4-Negative Cells via CCR5 and CXCR4: Comparison with HIV-1 and Simian Immunodeficiency Virus and Relevance to Cell Tropism In Vivo. J. Virol. 73: 7795-7804 [Abstract] [Full Text]  
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• Blanpain, C., Lee, B., Vakili, J., Doranz, B. J., Govaerts, C., Migeotte, I., Sharron, M., Dupriez, V., Vassart, G., Doms, R. W., Parmentier, M. (1999). Extracellular Cysteines of CCR5 Are Required for Chemokine Binding, but Dispensable for HIV-1 Coreceptor Activity. J. Biol. Chem. 274: 18902-18908 [Abstract] [Full Text]  
• Esté, J. A., Cabrera, C., Blanco, J., Gutierrez, A., Bridger, G., Henson, G., Clotet, B., Schols, D., De Clercq, E. (1999). Shift of Clinical Human Immunodeficiency Virus Type 1 Isolates from X4 to R5 and Prevention of Emergence of the Syncytium-Inducing Phenotype by Blockade of CXCR4. J. Virol. 73: 5577-5585 [Abstract] [Full Text]  
• Yang, O. O., Swanberg, S. L., Lu, Z., Dziejman, M., McCoy, J., Luster, A. D., Walker, B. D., Herrmann, S. H. (1999). Enhanced Inhibition of Human Immunodeficiency Virus Type 1 by Met-Stromal-Derived Factor 1beta Correlates with Down-Modulation of CXCR4. J. Virol. 73: 4582-4589 [Abstract] [Full Text]  
• Kawabata, K., Ujikawa, M., Egawa, T., Kawamoto, H., Tachibana, K., Iizasa, H., Katsura, Y., Kishimoto, T., Nagasawa, T. (1999). A cell-autonomous requirement for CXCR4 in long-term lymphoid and myeloid reconstitution. Proc. Natl. Acad. Sci. USA 96: 5663-5667 [Abstract] [Full Text]  
• Baba, M., Nishimura, O., Kanzaki, N., Okamoto, M., Sawada, H., Iizawa, Y., Shiraishi, M., Aramaki, Y., Okonogi, K., Ogawa, Y., Meguro, K., Fujino, M. (1999). A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc. Natl. Acad. Sci. USA 96: 5698-5703 [Abstract] [Full Text]  
• Richardson, J., Pancino, G., Merat, R., Leste-Lasserre, T., Moraillon, A., Schneider-Mergener, J., Alizon, M., Sonigo, P., Heveker, N. (1999). Shared Usage of the Chemokine Receptor CXCR4 by Primary and Laboratory-Adapted Strains of Feline Immunodeficiency Virus. J. Virol. 73: 3661-3671 [Abstract] [Full Text]  
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