title: Iron chelators ICL670 and 311 inhibit HIV-1 transcription.
abstract: HIV-1 replication is induced by an excess of iron and iron chelation by desferrioxamine (DFO) inhibits viral replication by reducing proliferation of infected cells. Treatment of cells with DFO and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) inhibit expression of proteins that regulate cell-cycle progression, including cycle-dependent kinase 2 (CDK2). Our recent studies showed that CDK2 participates in HIV-1 transcription and viral replication suggesting that inhibition of CDK2 by iron chelators might also affect HIV-1 transcription. Here we evaluated the effect of a clinically approved orally effective iron chelator, 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid (ICL670) and 311 on HIV-1 transcription. Both ICL670 and 311 inhibited Tat-induced HIV-1 transcription in CEM-T cells, 293T and HeLa cells. Neither ICL670 nor 311 induced cytotoxicity at concentrations that inhibited HIV-1 transcription. The chelators decreased cellular activity of CDK2 and reduced HIV-1 Tat phosphorylation by CDK2. Neither ICL670A or 311 decreased CDK9 protein level but significantly reduced association of CDK9 with cyclin T1 and reduced phosphorylation of Ser-2 residues of RNA polymerase II C-terminal domain. In conclusion, our findings add to the evidence that iron chelators can inhibit HIV-1 transcription by deregulating CDK2 and CDK9. Further consideration should be given to the development of iron chelators for future anti-retroviral therapeutics.
authors.affiliation: Center for Sickle Cell Disease, Howard University College of Medicine, Washington, DC 20060, USA.
authors.forename: Zufan
authors.initials: Z
authors.lastname: Debebe
authors.forename: Tatyana
authors.initials: T
authors.lastname: Ammosova
authors.forename: Marina
authors.initials: M
authors.lastname: Jerebtsova
authors.forename: Joseph
authors.initials: J
authors.lastname: Kurantsin-Mills
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Niu
authors.forename: Sharroya
authors.initials: S
authors.lastname: Charles
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
authors.forename: Patricio E
authors.initials: PE
authors.lastname: Ray
authors.forename: Victor R
authors.initials: VR
authors.lastname: Gordeuk
authors.forename: Sergei
authors.initials: S
authors.lastname: Nekhai
mesh_terms: D001565:Benzoates / Q000494:pharmacology*; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D000077588:Deferasirox; D015967:Gene Expression Regulation, Viral; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D007538:Isoniazid / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C120275:2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone; D001565:Benzoates; D007502:Iron Chelating Agents; D014230:Triazoles; D007501:Iron; D051357:Cyclin-Dependent Kinase 2; D042863:Cyclin-Dependent Kinase 9; D007538:Isoniazid; D000077588:Deferasirox