title: The antiviral activity of the CXCR4 antagonist AMD3100 is independent of the cytokine-induced CXCR4/HIV coreceptor expression level.
abstract: The chemokine receptor CXCR4 is the main coreceptor used by T-tropic X4 HIV-1 strains to infect its target T cells. It has been proven that the CXCR4 expression level in T cells is strongly up-regulated by interleukin (IL)-4, a Th2-type cytokine that is secreted preferentially in HIV-infected patients in a later stage of disease. This results in an enhancement of HIV-1 replication in CD4+ T-lymphocytes. We have now evaluated the potency of the CXCR4 antagonist AMD3100 in phytohemagglutinin (PHA)/IL-2- versus PHA/IL-4-activated T cells in order to determine whether the compound has comparable CXCR4-antagonistic and anti-HIV-1 effects under these different cytokine treatments. We analyzed the CXCR4 expression level and the dose-dependent inhibition of CXCR4 expression by AMD3100, by monitoring the binding of an anti-CXCR4 monoclonal antibody (clone 12G5). We also determined stromal cell-derived factor (SDF)-1-induced intracellular calcium signaling and HIV-1 replication in these cells in the absence and presence of AMD3100. The CXCR4 expression level in PHA/IL-4-stimulated cells was much higher than in PHA/IL-2-stimulated cells. However, the potency of the bicyclam AMD3100 to block anti-CXCR4 mAb binding, SDF-1-induced intracellular calcium signaling, and HIV-1 replication of the X4 NL4.3 strain and three primary isolates remained unchanged. Our data indicate that CXCR4 antagonists such as AMD3100 act independently of the HIV-1 coreceptor expression level. These compounds should therefore be useful in suppressing HIV-1 infection in all stages of the disease.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Department of Virology and Chemotherapy, Ninderbroedersstraat 10, B-3000 Leuven, Belgium. Katrien.Princen@rega.kuleuven.ac.be
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: Gary J
authors.initials: GJ
authors.lastname: Bridger
authors.forename: Renato T
authors.initials: RT
authors.lastname: Skerlj
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D001596:Benzylamines; D000080027:Cyclams; D016207:Cytokines / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D019380:Anti-HIV Agents; D001596:Benzylamines; D000080027:Cyclams; D016207:Cytokines; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D011991:Receptors, Virus; C088327:plerixafor