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.

Phenyl-1-Pyridin-2yl-Ethanone-Based Iron Chelators Increase IκB-α Expression, Modulate CDK2 and CDK9 Activities, and Inhibit HIV-1 Transcription

“…The expression of p21 was also shown to be increased by HIF-1␣, which displaced c-myc on the p21 promoter (43). We previously demonstrated that the iron chelators 311, ICL670, Bp4eT, and Dp4eT inhibit the activity of CDK2 (15,16). Here we showed that PPY-based iron chelators inhibited cell cycle progression of promonocytic THP-1 cells, CEM T cells, and epithelial 293T cells.…”

“…While we could not detect changes in the p21 expression levels, our previous studies suggested that CDK2 activity is reduced by chelator-treated cells (15,16). To determine whether the PPY-based iron chelators inhibit CDK2 activity, 293T cells were cultured for 48 h at 37°C in the presence or absence of the iron chelators, using the PPY compound as a control.…”

“…We previously described a role of iron chelators in the inhibition of HIV-1 transcription and replication, likely by reducing the activities of CDK2 and CDK9 (15,16); however, the exact mechanism of action has remained unclear. Induction of p21 (CIP1/ WAF1) expression by iron chelators was recently shown to inhibit CDK2 activity in 293T cells (17)(18)(19).…”

Potent Antimycobacterial Activity of the Pyridoxal Isonicotinoyl Hydrazone Analog 2-Pyridylcarboxaldehyde Isonicotinoyl Hydrazone: A Lipophilic Transport Vehicle for Isonicotinic Acid Hydrazide

“…The importance of iron for mycobacterial growth suggests a potential role for chelation therapy as a treatment option. Indeed, the use of iron chelation as a potential therapy for infectious diseases has been well documented, including the in vitro use of chelators to inhibit viral replication and reverse transcriptase activity in human immunodeficiency virus treatment (Debebe et al, 2007;Traore and Meyer, 2007). Furthermore, in malarial infection, chelation therapy increased parasite clearance rate (Pradines et al, 2002;Walcourt et al, 2004).…”

Short Communication: High Cellular Iron Levels Are Associated with Increased HIV Infection and Replication

“…12 However, another study found no change in NF-jB with iron chelation. 13 A reduction in cyclin-dependent kinase (CDK) 2/cyclin E complex activity has also been suggested as one of the mechanisms of how iron deficiency reduces HIV replication, 11,14 but changes in CDK2/cyclin E complex activity were not observed in another study using DFO to decrease cellular iron. 15 Therefore, the interaction between HIV infection and cellular and systemic iron status, particularly in the post-ART era, remains unclear.…”