INHIBITION OF T-TROPIC HIV STRAINS BY SELECTIVE ANTAGONIZATION OF THECHEMOKINE RECEPTOR CXCR4

Bicyclams are a novel class of antiviral compounds that are highly pot ent and selective inhibitors of the replication of HIV-I and HIV-2. Su rprisingly, however, when the prototype compound AMD3100 was tested ag ainst M-tropic virus strains such as Bat, ADA,JR-CSF, and SF-162 in hu man peripheral blood mononuclear cells, the compound was completely in active. Because of the specific and potent inhibitory effect of AMD310 0 on T-tropic viruses, but not M-tropic viruses, it was verified that AMD3100 interacts with the CXC-chemokine receptor CXCR4, the main core ceptor used by T-tropic viruses. AMD3100 dose dependently inhibited th e binding of a specific CXCR4 monoclonal antibody to SUP-T1 cells as m easured by flow cytometry. It did not inhibit the binding of the bioti nylated CC-chemokine macrophage inflammatory protein (MIP) 1 alpha or MIP-1 beta, ligands for the chemokine receptor CCR5 (the main corecept or 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 c ells, and (b) the chemotactic responses of THP-1 cells induced by stro mal 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 secre ted (RANTES; also a ligand for CCR5), or monocyte chemoattractant prot ein 3 (a ligand for CCR1 and CCR2b), nor was it able to induce Ca2+ fl uxes by itself The bicyclams are, to our knowledge, the first low mole cular weight anti-HIV agents shown to act as potent and selective CXCR 4 antagonists.