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

<p>Abstract</p> <p>Background</p> <p>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 cataly...

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Main Authors: Saxena Deepti, Palumbo Paul, Hanauske-Abel Hartmut M, Hoque Mainul, D'Alliessi Gandolfi Darlene, Park Myung, Pe'ery Tsafi, Mathews Michael B
Format: Article
Language:English
Published: BMC 2009-10-01
Series:Retrovirology
Online Access:http://www.retrovirology.com/content/6/1/90
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spelling doaj-d146472d3ad64bf6bcac263c5c390d572020-11-24T23:29:23ZengBMCRetrovirology1742-46902009-10-01619010.1186/1742-4690-6-90Inhibition of HIV-1 gene expression by Ciclopirox and Deferiprone, drugs that prevent hypusination of eukaryotic initiation factor 5ASaxena DeeptiPalumbo PaulHanauske-Abel Hartmut MHoque MainulD'Alliessi Gandolfi DarlenePark MyungPe'ery TsafiMathews Michael B<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>At clinically relevant concentrations, two widely used drugs blocked HIV-1 replication <it>ex vivo</it>. 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.</p> http://www.retrovirology.com/content/6/1/90
collection DOAJ
language English
format Article
sources DOAJ
author Saxena Deepti
Palumbo Paul
Hanauske-Abel Hartmut M
Hoque Mainul
D'Alliessi Gandolfi Darlene
Park Myung
Pe'ery Tsafi
Mathews Michael B
spellingShingle Saxena Deepti
Palumbo Paul
Hanauske-Abel Hartmut M
Hoque Mainul
D'Alliessi Gandolfi Darlene
Park Myung
Pe'ery Tsafi
Mathews Michael B
Inhibition of HIV-1 gene expression by Ciclopirox and Deferiprone, drugs that prevent hypusination of eukaryotic initiation factor 5A
Retrovirology
author_facet Saxena Deepti
Palumbo Paul
Hanauske-Abel Hartmut M
Hoque Mainul
D'Alliessi Gandolfi Darlene
Park Myung
Pe'ery Tsafi
Mathews Michael B
author_sort Saxena Deepti
title Inhibition of HIV-1 gene expression by Ciclopirox and Deferiprone, drugs that prevent hypusination of eukaryotic initiation factor 5A
title_short Inhibition of HIV-1 gene expression by Ciclopirox and Deferiprone, drugs that prevent hypusination of eukaryotic initiation factor 5A
title_full Inhibition of HIV-1 gene expression by Ciclopirox and Deferiprone, drugs that prevent hypusination of eukaryotic initiation factor 5A
title_fullStr Inhibition of HIV-1 gene expression by Ciclopirox and Deferiprone, drugs that prevent hypusination of eukaryotic initiation factor 5A
title_full_unstemmed Inhibition of HIV-1 gene expression by Ciclopirox and Deferiprone, drugs that prevent hypusination of eukaryotic initiation factor 5A
title_sort inhibition of hiv-1 gene expression by ciclopirox and deferiprone, drugs that prevent hypusination of eukaryotic initiation factor 5a
publisher BMC
series Retrovirology
issn 1742-4690
publishDate 2009-10-01
description <p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>At clinically relevant concentrations, two widely used drugs blocked HIV-1 replication <it>ex vivo</it>. 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.</p>
url http://www.retrovirology.com/content/6/1/90
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