Inhibition of HIV-1 gene expression by Ciclopirox and Deferiprone, drugs that prevent hypusination of eukaryotic initiation factor 5A.
BACKGROUND
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). 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.


RESULTS
Ciclopirox 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.


CONCLUSIONS
At 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.
Hoque
Mainul
M
Department of Biochemistry & Molecular Biology, UMDNJ-New Jersey Medical School, NJ 07103, USA.
Hanauske-Abel
Hartmut M
HM
Palumbo
Paul
P
Saxena
Deepti
D
D'Alliessi Gandolfi
Darlene
D
Park
Myung Hee
MH
Pe'ery
Tsafi
T
Mathews
Michael B
MB
D019380:Anti-HIV Agents / Q000494:pharmacology*; D000077768:Ciclopirox; D000077543:Deferiprone; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D010448:Peptide Initiation Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D000097574:Eukaryotic Translation Initiation Factor 5A
D019380:Anti-HIV Agents; D000077768:Ciclopirox; D000077543:Deferiprone; D004791:Enzyme Inhibitors; D008239:Lysine; D006899:Mixed Function Oxygenases; D010448:Peptide Initiation Factors; D011728:Pyridones; D016601:RNA-Binding Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A; C100028:hypusine; C047991:deoxyhypusine hydroxylase