Abstract
BackgroundEukaryotic translation initiation factor eIF5A has been implicated in HIV-1 replication. This protein contains the apparently unique amino acid hypusine that is formed by the post-translational modification of a lysine residue catalyzed by deoxyhypusine synthase and deoxyhypusine hydroxylase (DOHH). DOHH activity is inhibited by two clinically used drugs, the topical fungicide ciclopirox and the systemic medicinal iron chelator deferiprone. Deferiprone has been reported to inhibit HIV-1 replication in tissue culture.ResultsCiclopirox and deferiprone blocked HIV-1 replication in PBMCs. To examine the underlying mechanisms, we investigated the action of the drugs on eIF5A modification and HIV-1 gene expression in model systems. At early times after drug exposure, both drugs inhibited substrate binding to DOHH and prevented the formation of mature eIF5A. Viral gene expression from HIV-1 molecular clones was suppressed at the RNA level independently of all viral genes. The inhibition was specific for the viral promoter and occurred at the level of HIV-1 transcription initiation. Partial knockdown of eIF5A-1 by siRNA led to inhibition of HIV-1 gene expression that was non-additive with drug action. These data support the importance of eIF5A and hypusine formation in HIV-1 gene expression.ConclusionAt clinically relevant concentrations, two widely used drugs blocked HIV-1 replication ex vivo. They specifically inhibited expression from the HIV-1 promoter at the level of transcription initiation. Both drugs interfered with the hydroxylation step in the hypusine modification of eIF5A. These results have profound implications for the potential therapeutic use of these drugs as antiretrovirals and for the development of optimized analogs.
Highlights
Eukaryotic translation initiation factor eIF5A has been implicated in human immunodeficiency virus type 1 (HIV-1) replication
Despite the success of combinations of these drugs in highly active antiretroviral therapy (HAART), the emergence of drug-resistant HIV-1 strains that are facilitated by the high mutation and recombination rates of the virus in conjunction with its prolific replication poses a serious limitation to current treatments
Antiviral activity of ciclopirox and deferiprone To examine the effect of CPX and DEF on HIV-1 propagation, uninfected peripheral blood mononuclear cells (PBMCs) from healthy donors were co-cultured with HIV-infected PBMCs, and virus production was monitored by the p24 capture assay
Summary
Eukaryotic translation initiation factor eIF5A has been implicated in HIV-1 replication. This protein contains the apparently unique amino acid hypusine that is formed by the post-translational modification of a lysine residue catalyzed by deoxyhypusine synthase and deoxyhypusine hydroxylase (DOHH). Since its discovery in 1981, human immunodeficiency virus type 1 (HIV-1) has led to the death of at least 25 million people worldwide. Studies of the HIV-1 life cycle led to the development of drugs targeting viral proteins important for viral infection, most notably reverse transcriptase and protease inhibitors. Despite the success of combinations of these drugs in highly active antiretroviral therapy (HAART), the emergence of drug-resistant HIV-1 strains that are facilitated by the high mutation and recombination rates of the virus in conjunction with its prolific replication poses a serious limitation to current treatments. An attractive strategy to circumvent this problem entails targeting host factors that are recruited by the virus to complete its life cycle
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