title: Inhibition of human immunodeficiency virus replication by a dual CCR5/CXCR4 antagonist.
abstract: 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 [IC(50)] ranging from 1.2 to 26.5 microM) 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 (IC(50), 1.8 to 7.3 microM). 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 Ca(2+) signaling induced by the CXCR4 ligand CXCL12 in T-lymphocytic cells and in CXCR4-transfected cells, as well as the Ca(2+) flux induced by the CCR5 ligands CCL5, CCL3, and CCL4 in CCR5-transfected cells. The compound did not interfere with chemokine-induced Ca(2+) signaling through CCR1, CCR2, CCR3, CCR4, CCR6, CCR9, or CXCR3 and did not induce intracellular Ca(2+) signaling by itself at concentrations up to 400 microM. In freshly isolated monocytes, AMD3451 inhibited the Ca(2+) 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.
authors.affiliation: Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Princen
authors.forename: Sigrid
authors.initials: S
authors.lastname: Hatse
authors.forename: Kurt
authors.initials: K
authors.lastname: Vermeire
authors.forename: Stefano
authors.initials: S
authors.lastname: Aquaro
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Lars-Ole
authors.initials: LO
authors.lastname: Gerlach
authors.forename: Mette
authors.initials: M
authors.lastname: Rosenkilde
authors.forename: Thue W
authors.initials: TW
authors.lastname: Schwartz
authors.forename: Renato
authors.initials: R
authors.lastname: Skerlj
authors.forename: Gary
authors.initials: G
authors.lastname: Bridger
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology; D065100:CCR5 Receptor Antagonists; D002118:Calcium / Q000378:metabolism; D054377:Chemokine CXCL12; D019742:Chemokines, CC / Q000037:antagonists & inhibitors; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors; D002633:Chemotaxis / Q000187:drug effects; D006678:HIV / Q000187:drug effects* / Q000502:physiology; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D011725:Pyridines / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C493591:1-((2,6-dichloropyridin-4-yl)methyl)-1,4,8,11-tetrazacyclotetradecane; D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; C492767:CCL3L1 protein, human; D065100:CCR5 Receptor Antagonists; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019742:Chemokines, CC; D019743:Chemokines, CXC; D006571:Heterocyclic Compounds; D011725:Pyridines; D019718:Receptors, CXCR4; D002118:Calcium