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Journal of Virology, December 2004, p. 12996-13006, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.12996-13006.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Inhibition of Human Immunodeficiency Virus Replication by a Dual CCR5/CXCR4 Antagonist

Katrien Princen,¹ Sigrid Hatse,¹ Kurt Vermeire,¹ Stefano Aquaro,^1, Erik De Clercq,¹ Lars-Ole Gerlach,² Mette Rosenkilde,² Thue W. Schwartz,² Renato Skerlj,³ Gary Bridger,³ and Dominique Schols^1*

Rega Institute for Medical Research, Leuven, Belgium,¹ The Panum Institute, Copenhagen, Denmark,² AnorMED, Langley, British Columbia, Canada³

Received 4 May 2004/ Accepted 30 June 2004

Here we report that the N-pyridinylmethyl cyclam analog AMD3451 has antiviral activity against a wide variety of R5, R5/X4, and X4 strains of human immunodeficiency virus type 1 (HIV-1) and HIV-2 (50% inhibitory concentration [IC₅₀] ranging from 1.2 to 26.5 µM) in various T-cell lines, CCR5- or CXCR4-transfected cells, peripheral blood mononuclear cells (PBMCs), and monocytes/macrophages. AMD3451 also inhibited R5, R5/X4, and X4 HIV-1 primary clinical isolates in PBMCs (IC₅₀, 1.8 to 7.3 µM). A PCR-based viral entry assay revealed that AMD3451 blocks R5 and X4 HIV-1 infection at the virus entry stage. AMD3451 dose-dependently inhibited the intracellular Ca²⁺ signaling induced by the CXCR4 ligand CXCL12 in T-lymphocytic cells and in CXCR4-transfected cells, as well as the Ca²⁺ flux induced by the CCR5 ligands CCL5, CCL3, and CCL4 in CCR5-transfected cells. The compound did not interfere with chemokine-induced Ca²⁺ signaling through CCR1, CCR2, CCR3, CCR4, CCR6, CCR9, or CXCR3 and did not induce intracellular Ca²⁺ signaling by itself at concentrations up to 400 µM. In freshly isolated monocytes, AMD3451 inhibited the Ca²⁺ flux induced by CXCL12 and CCL4 but not that induced by CCL2, CCL3, CCL5, and CCL7. The CXCL12- and CCL3-induced chemotaxis was also dose-dependently inhibited by AMD3451. Furthermore, AMD3451 inhibited CXCL12- and CCL3L1-induced endocytosis in CXCR4- and CCR5-transfected cells. AMD3451, in contrast to the specific CXCR4 antagonist AMD3100, did not inhibit but enhanced the binding of several anti-CXCR4 monoclonal antibodies (such as clone 12G5) at the cell surface, pointing to a different interaction with CXCR4. AMD3451 is the first low-molecular-weight anti-HIV agent with selective HIV coreceptor, CCR5 and CXCR4, interaction.

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* Corresponding author. Mailing address: 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.

Present address: Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome 00133, Italy.

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Journal of Virology, December 2004, p. 12996-13006, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.12996-13006.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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