Iron chelators ICL670 and 311 inhibit HIV-1 transcription

• Published in: Virology (New York, N.Y.) N.Y.), 2007-10, Vol.367 (2), p.324-333
• Main Authors: Debebe, Zufan, Ammosova, Tatyana, Jerebtsova, Marina, Kurantsin-Mills, Joseph, Niu, Xiaomei, Charles, Sharroya, Richardson, Des R, Ray, Patricio E, Gordeuk, Victor R, Nekhai, Sergei
• Format: Article
• Language: English
• Subjects: 2-Hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone; 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid (ICL670); 60 APPLIED LIFE SCIENCES; AIDS VIRUS; Benzoates - pharmacology; BENZOIC ACID; CDK2; CDK9; CELL CYCLE; CELL PROLIFERATION; Cells, Cultured; Cyclin-Dependent Kinase 2 - metabolism; Cyclin-Dependent Kinase 9 - metabolism; Desferrioxamine (DFO); Gene Expression Regulation, Viral; HELA CELLS; HIV-1; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 - immunology; Humans; HYDRAZONES; Infectious Disease; INHIBITION; IRON; Iron - metabolism; Iron Chelating Agents - chemistry; Iron Chelating Agents - pharmacology; Iron chelation; Isoniazid - pharmacology; PHOSPHORYLATION; RNA POLYMERASES; TOXICITY; TRANSCRIPTION; Transcription, Genetic - drug effects; Transcription, Genetic - physiology; Triazoles - pharmacology; Virus Replication - drug effects
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2007.06.011

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.