Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4
(1997) The Journal of Experimental Medicine — Vol. 186, n° 8, p. 1383-1388 (1997)
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- Abstract
- Bicyclams are a novel class of antiviral compounds that are highly potent and selective inhibitors of the replication of HIV-I and HIV-2. Surprisingly, however, when the prototype compound AMD3100 was tested against M-tropic virus strains such as Bat, 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-1 beta, 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-TI 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.
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Schols, D., Struyf, S., Vandamme, J., Este, J., Henson, G., & De Clercq, E. (1997). Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4. The Journal of Experimental Medicine, 186(8), 1383-1388. https://doi.org/10.1084/jem.186.8.1383 (Original work published 1997)