Iron chelators ICL670 and 311 inhibit HIV-1 transcription
- Center for Sickle Cell Disease, Howard University College of Medicine, 520 W. St., N.W., Washington, DC 20060 (United States)
- Children's National Medical Center, CRI Center for Cancer and Immunology, 111 Michigan Ave., N.W., Washington, DC 20060 (United States)
- Department of Biophysics and Physiology, Howard University College of Medicine, 520 W. St., N.W., Washington, DC 20060 (United States)
- Iron Metabolism and Chelation Program, Department of Pathology, Blackburn Building (D06), University of Sydney, Sydney, New South Wales, 2006 Australia (Australia)
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.
- OSTI ID:
- 21077984
- Journal Information:
- Virology, Vol. 367, Issue 2; Other Information: DOI: 10.1016/j.virol.2007.06.011; PII: S0042-6822(07)00416-3; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0042-6822
- Country of Publication:
- United States
- Language:
- English
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