HIV-1 replication is induced by the excess of iron and iron chelation by desferrioxamine (DFO) inhibits viral replication in HIV-1 infected CEM T cells [1]. Treatment of cells with DFO or 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone inhibits expression of proteins that regulate cell-cycle progression, including cycle-dependent kinase 2 (CDK2) [2]. HIV-1 transcription is activated by Tat protein, which recruits transcriptional co-activators to the HIV-1 promoter. Elongation of HIV-1 transcription is mediated by the interaction of HIV Tat with host cell cycle-dependent kinase 9 (CDK9)/cyclin T1, which phosphorylates the C-terminal domain of RNA polymerase II. Our recent studies showed that CDK2 participates in HIV-1 transcription by phosphorylating Tat [3]. Thus inhibition of CDK2 by iron chelators might present a new approach to inhibit HIV-1 transcription. 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 or deferasirox) on HIV-1 transcription. ICL670 inhibited Tat-induced HIV-1 transcription in CEM, 293T and HeLa cells at concentrations that did not induce cytotoxicity. The chelator decreased cellular activity of CDK2 but not its protein level and reduced HIV-1 Tat phosphorylation by CDK2. ICL670 did not decrease 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 may inhibit HIV-1 transcription by deregulating CDK2 and Cdk9. Further consideration should be given to the evaluation of ICL670 for future anti-retroviral therapeutics and to the development of iron chelators specifically as anti-retroviral agents.


Traore, H. N. & Meyer, D. (
) The effect of iron overload on in vitro HIV-1 infection,
J Clin Virol.
Suppl 1,
Gao, J. & Richardson, D. R. (
) The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents, IV: The mechanisms involved in inhibiting cell-cycle progression,
Ammosova, T., Berro, R., Jerebtsova, M., Jackson, A., Charles, S., Klase, Z., Southerland, W., Gordeuk, V. R., Kashanchi, F. & Nekhai, S. (
) Phosphorylation of HIV-1 Tat by CDK2 in HIV-1 transcription,

Author notes

Disclosure: No relevant conflicts of interest to declare.