Proteomics

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An integrated systems biology approach reveals positive and negative effects of suberoylanilide hydroxamic acid (SAHA) on HIV reactivation from latency


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 the reduction of reservoir size "kill". We therefore utilized a systems biology approach to dissect the mechanisms of action of SAHA that may explain its limited success in “shock and kill” strategies. CD4+ T cells from HIV seronegative donors were treated with 1 uM SAHA or its solvent dimethyl sulfoxide for 24 hours. Differential protein expression and post-translational modification was measured with two-dimensional liquid chromatography - tandem mass spectrometry iTRAQ proteomics. Gene expression changes were assessed by Illumina microarrays. Using limma package in the R computing environment, we identified 185 proteins, 18 phosphorylated forms, 4 acetylated forms and 2,982 genes, whose expression was modulated by SAHA. A protein interaction network integrating these 4 data types identified the transcriptional regulator HMGA1 to be upregulated by SAHA at the transcript, protein and acetylated protein levels. HMGA1 has been shown to repress HIV transcription, which is not optimal with respect to a shock and kill strategy. Further functional category assessment of proteins and genes modulated by SAHA identified gene ontology terms related to NFB signaling, protein folding and autophagy, which are all relevant to HIV reactivation. In summary, this study identified a number of host factors that may be therapeutically targeted to achieve more potent HIV reactivation in the “shock and kill” treatment, when using SAHA, either through modification of SAHA itself or through combination with other latency reversing agents. Finally, proteome profiling highlighted a number of potential adverse effects of SAHA, which transcriptome profiling alone would not have identified.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, T-lymphocyte

DISEASE(S): Human Immunodeficiency Virus Infectious Disease

SUBMITTER: Harvey Johnston  

LAB HEAD: Spiros D. Garbis

PROVIDER: PXD002150 | Pride | 2015-09-10

REPOSITORIES: Pride

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Publications

Mixed effects of suberoylanilide hydroxamic acid (SAHA) on the host transcriptome and proteome and their implications for HIV reactivation from latency.

White Cory H CH   Johnston Harvey E HE   Moesker Bastiaan B   Manousopoulou Antigoni A   Margolis David M DM   Richman Douglas D DD   Spina Celsa A CA   Garbis Spiros D SD   Woelk Christopher H CH   Beliakova-Bethell Nadejda N  

Antiviral research 20150904


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  ...[more]

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