Mixed effects of suberoylanilide hydroxamic acid (SAHA) on the host transcriptome and proteome and their implications for HIV reactivation from latency
Mixed effects of suberoylanilide hydroxamic acid (SAHA) on the host transcriptome and proteome and their implications for HIV reactivation from latency
Suberoylanilide hydroxamic acid (SAHA) has been assessed in clinical trials as part of a “shock and kill” strategy to cure HIV-infected patients. While it was effective at inducing expression of HIV RNA (“shock”), treatment with SAHA did not result in a reduction of reservoir size (“kill”). We therefore utilized a combined analysis of effects of SAHA on the host transcriptome and proteome to dissect its mechanisms of action that may explain its limited success in “shock and kill” strategies. CD4+ T cells from HIV seronegative donors were treated with 1 ?M SAHA or its solvent dimethyl sulfoxide (DMSO) for 24 h. Protein expression and post-translational modifications were measured with iTRAQ proteomics using ultra high-precision two-dimensional liquid chromatography–tandem mass spectrometry. Gene expression was assessed by Illumina microarrays. Using limma package in the R computing environment, we identified 185 proteins, 18 phosphorylated forms, 4 acetylated forms and 2982 genes, whose expression was modulated by SAHA. A protein interaction network integrating these 4 data types identified the HIV transcriptional repressor HMGA1 to be upregulated by SAHA at the transcript, protein and acetylated protein levels. Further functional category assessment of proteins and genes modulated by SAHA identified gene ontology terms related to NF?B signaling, protein folding and autophagy, which are all relevant to HIV reactivation. In summary, SAHA modulated numerous host cell transcripts, proteins and post-translational modifications of proteins, which would be expected to have very mixed effects on the induction of HIV-specific transcription and protein function. Proteome profiling highlighted a number of potential counter-regulatory effects of SAHA with respect to viral induction, which transcriptome profiling alone would not have identified. These observations could lead to a more informed selection and design of other HDACi with a more refined targeting profile, and prioritization of latency reversing agents of other classes to be used in combination with SAHA to achieve more potent induction of HIV expression.
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White, Cory H.
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Johnston, Harvey E.
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Moesker, Bastiaan
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Manousopoulou, Antigoni
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Margolis, David M.
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Richman, Douglas D.
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Spina, Celsa A.
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Garbis, Spiros D.
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Woelk, Christopher
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Beliakova-Bethell, Nadejda
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1 November 2015
White, Cory H.
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Johnston, Harvey E.
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Moesker, Bastiaan
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Manousopoulou, Antigoni
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Margolis, David M.
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Richman, Douglas D.
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Spina, Celsa A.
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Garbis, Spiros D.
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Woelk, Christopher
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Beliakova-Bethell, Nadejda
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White, Cory H., Johnston, Harvey E., Moesker, Bastiaan, Manousopoulou, Antigoni, Margolis, David M., Richman, Douglas D., Spina, Celsa A., Garbis, Spiros D., Woelk, Christopher and Beliakova-Bethell, Nadejda
(2015)
Mixed effects of suberoylanilide hydroxamic acid (SAHA) on the host transcriptome and proteome and their implications for HIV reactivation from latency.
Antiviral Research, 123, .
(doi:10.1016/j.antiviral.2015.09.002).
(PMID:26343910)
Abstract
Suberoylanilide hydroxamic acid (SAHA) has been assessed in clinical trials as part of a “shock and kill” strategy to cure HIV-infected patients. While it was effective at inducing expression of HIV RNA (“shock”), treatment with SAHA did not result in a reduction of reservoir size (“kill”). We therefore utilized a combined analysis of effects of SAHA on the host transcriptome and proteome to dissect its mechanisms of action that may explain its limited success in “shock and kill” strategies. CD4+ T cells from HIV seronegative donors were treated with 1 ?M SAHA or its solvent dimethyl sulfoxide (DMSO) for 24 h. Protein expression and post-translational modifications were measured with iTRAQ proteomics using ultra high-precision two-dimensional liquid chromatography–tandem mass spectrometry. Gene expression was assessed by Illumina microarrays. Using limma package in the R computing environment, we identified 185 proteins, 18 phosphorylated forms, 4 acetylated forms and 2982 genes, whose expression was modulated by SAHA. A protein interaction network integrating these 4 data types identified the HIV transcriptional repressor HMGA1 to be upregulated by SAHA at the transcript, protein and acetylated protein levels. Further functional category assessment of proteins and genes modulated by SAHA identified gene ontology terms related to NF?B signaling, protein folding and autophagy, which are all relevant to HIV reactivation. In summary, SAHA modulated numerous host cell transcripts, proteins and post-translational modifications of proteins, which would be expected to have very mixed effects on the induction of HIV-specific transcription and protein function. Proteome profiling highlighted a number of potential counter-regulatory effects of SAHA with respect to viral induction, which transcriptome profiling alone would not have identified. These observations could lead to a more informed selection and design of other HDACi with a more refined targeting profile, and prioritization of latency reversing agents of other classes to be used in combination with SAHA to achieve more potent induction of HIV expression.
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Mixed effects of suberoylanilide hydroxamic acid (SAHA) on the host transcriptome and proteome and their implications for HIV reactivation from latency.pdf
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Accepted/In Press date: 3 September 2015
e-pub ahead of print date: 4 September 2015
Published date: 1 November 2015
Organisations:
Cancer Sciences, Human Development & Health
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Local EPrints ID: 395375
URI: http://eprints.soton.ac.uk/id/eprint/395375
ISSN: 0166-3542
PURE UUID: 0440c222-0882-47f4-a1a3-55e389345318
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Date deposited: 27 May 2016 13:13
Last modified: 15 Mar 2024 00:39
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Author:
Cory H. White
Author:
Harvey E. Johnston
Author:
Bastiaan Moesker
Author:
Antigoni Manousopoulou
Author:
David M. Margolis
Author:
Douglas D. Richman
Author:
Celsa A. Spina
Author:
Spiros D. Garbis
Author:
Christopher Woelk
Author:
Nadejda Beliakova-Bethell
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