Entinostat is a histone deacetylase inhibitor selective for class 1 histone deacetylases and activates HIV production from latently infected primary T cells

Fiona Wightman, Hao Kim Lu, Ajantha Solomon, Suha Mahdi Saleh, Andrew N Harman, Anthony L Cunningham, Lachlan Robert Gray, Melissa Churchill, Paul Urquhart Cameron, Anthony Edwin Dear, Sharon Ruth Lewin

Research output: Contribution to journalArticleResearchpeer-review

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Abstract

Objectives: To compare the potency, toxicity and mechanism of action of multiple histone deacetylase inhibitors (HDACi) in activating HIV production from latency. Design: In-vitro analysis of HDACi in a primary T-cell model of HIV latency and latently infected cell lines. Methods: Latently infected chemokine ligand 19 (CCL19)-treated CD4 T cells and the latently infected cell lines ACH2 and J-Lat were treated with a panel of HDACi, including entinostat, vorinostat, panonbinostat and MCT3. Viral production and cell viability were compared. Expression of cellular HDACs was measured by western blot and PCR. Association of HDACs with the HIV long-terminal repeat (LTR) using latently infected CCL19-treated primary CD4 T cells in the presence and absence of specific HDACi was determined by chromatin immunoprecipitation (ChIP). Results: We demonstrated considerable variation in the potency and toxicity of HDACi in latently infected primary CD4 T cells and cell lines. All HDACi tested activated HIV production in latently infected primary T cells with greatest potency demonstrated with entinostat and vorinostat and greatest toxicity with panobinostat. Following the addition of HDACi in vitro, there were no changes in markers of T-cell activation or expression of the HIV coreceptors chemokine (C-X-C motif) receptor 4 (CXCR4) or chemokine (C-C motif) receptor type 5 (CCR5). ChIP analysis of latently infected CCL19-treated primary CD4 T cells showed binding by HDAC1, HDAC2 and HDAC3 to the LTR with removal of HDAC1 and HDAC2 following treatment with the HDACi vorinostat and HDAC1 only following treatment with entinostat. Conclusion: The HDACi entinostat, selective for inhibition of class I HDACs, induced virus expression in latently infected primary CD4 T cells making this compound an attractive novel option for future clinical trials. ? 2013 Wolters Kluwer Health Lippincott Williams Wilkins.
Original languageEnglish
Pages (from-to)2853 - 2862
Number of pages10
JournalAIDS
Volume27
Issue number18
DOIs
Publication statusPublished - 2013

Cite this

Wightman, Fiona ; Lu, Hao Kim ; Solomon, Ajantha ; Saleh, Suha Mahdi ; Harman, Andrew N ; Cunningham, Anthony L ; Gray, Lachlan Robert ; Churchill, Melissa ; Cameron, Paul Urquhart ; Dear, Anthony Edwin ; Lewin, Sharon Ruth. / Entinostat is a histone deacetylase inhibitor selective for class 1 histone deacetylases and activates HIV production from latently infected primary T cells. In: AIDS. 2013 ; Vol. 27, No. 18. pp. 2853 - 2862.
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title = "Entinostat is a histone deacetylase inhibitor selective for class 1 histone deacetylases and activates HIV production from latently infected primary T cells",
abstract = "Objectives: To compare the potency, toxicity and mechanism of action of multiple histone deacetylase inhibitors (HDACi) in activating HIV production from latency. Design: In-vitro analysis of HDACi in a primary T-cell model of HIV latency and latently infected cell lines. Methods: Latently infected chemokine ligand 19 (CCL19)-treated CD4 T cells and the latently infected cell lines ACH2 and J-Lat were treated with a panel of HDACi, including entinostat, vorinostat, panonbinostat and MCT3. Viral production and cell viability were compared. Expression of cellular HDACs was measured by western blot and PCR. Association of HDACs with the HIV long-terminal repeat (LTR) using latently infected CCL19-treated primary CD4 T cells in the presence and absence of specific HDACi was determined by chromatin immunoprecipitation (ChIP). Results: We demonstrated considerable variation in the potency and toxicity of HDACi in latently infected primary CD4 T cells and cell lines. All HDACi tested activated HIV production in latently infected primary T cells with greatest potency demonstrated with entinostat and vorinostat and greatest toxicity with panobinostat. Following the addition of HDACi in vitro, there were no changes in markers of T-cell activation or expression of the HIV coreceptors chemokine (C-X-C motif) receptor 4 (CXCR4) or chemokine (C-C motif) receptor type 5 (CCR5). ChIP analysis of latently infected CCL19-treated primary CD4 T cells showed binding by HDAC1, HDAC2 and HDAC3 to the LTR with removal of HDAC1 and HDAC2 following treatment with the HDACi vorinostat and HDAC1 only following treatment with entinostat. Conclusion: The HDACi entinostat, selective for inhibition of class I HDACs, induced virus expression in latently infected primary CD4 T cells making this compound an attractive novel option for future clinical trials. ? 2013 Wolters Kluwer Health Lippincott Williams Wilkins.",
author = "Fiona Wightman and Lu, {Hao Kim} and Ajantha Solomon and Saleh, {Suha Mahdi} and Harman, {Andrew N} and Cunningham, {Anthony L} and Gray, {Lachlan Robert} and Melissa Churchill and Cameron, {Paul Urquhart} and Dear, {Anthony Edwin} and Lewin, {Sharon Ruth}",
year = "2013",
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Wightman, F, Lu, HK, Solomon, A, Saleh, SM, Harman, AN, Cunningham, AL, Gray, LR, Churchill, M, Cameron, PU, Dear, AE & Lewin, SR 2013, 'Entinostat is a histone deacetylase inhibitor selective for class 1 histone deacetylases and activates HIV production from latently infected primary T cells', AIDS, vol. 27, no. 18, pp. 2853 - 2862. https://doi.org/10.1097/QAD.0000000000000067

Entinostat is a histone deacetylase inhibitor selective for class 1 histone deacetylases and activates HIV production from latently infected primary T cells. / Wightman, Fiona; Lu, Hao Kim; Solomon, Ajantha; Saleh, Suha Mahdi; Harman, Andrew N; Cunningham, Anthony L; Gray, Lachlan Robert; Churchill, Melissa; Cameron, Paul Urquhart; Dear, Anthony Edwin; Lewin, Sharon Ruth.

In: AIDS, Vol. 27, No. 18, 2013, p. 2853 - 2862.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Entinostat is a histone deacetylase inhibitor selective for class 1 histone deacetylases and activates HIV production from latently infected primary T cells

AU - Wightman, Fiona

AU - Lu, Hao Kim

AU - Solomon, Ajantha

AU - Saleh, Suha Mahdi

AU - Harman, Andrew N

AU - Cunningham, Anthony L

AU - Gray, Lachlan Robert

AU - Churchill, Melissa

AU - Cameron, Paul Urquhart

AU - Dear, Anthony Edwin

AU - Lewin, Sharon Ruth

PY - 2013

Y1 - 2013

N2 - Objectives: To compare the potency, toxicity and mechanism of action of multiple histone deacetylase inhibitors (HDACi) in activating HIV production from latency. Design: In-vitro analysis of HDACi in a primary T-cell model of HIV latency and latently infected cell lines. Methods: Latently infected chemokine ligand 19 (CCL19)-treated CD4 T cells and the latently infected cell lines ACH2 and J-Lat were treated with a panel of HDACi, including entinostat, vorinostat, panonbinostat and MCT3. Viral production and cell viability were compared. Expression of cellular HDACs was measured by western blot and PCR. Association of HDACs with the HIV long-terminal repeat (LTR) using latently infected CCL19-treated primary CD4 T cells in the presence and absence of specific HDACi was determined by chromatin immunoprecipitation (ChIP). Results: We demonstrated considerable variation in the potency and toxicity of HDACi in latently infected primary CD4 T cells and cell lines. All HDACi tested activated HIV production in latently infected primary T cells with greatest potency demonstrated with entinostat and vorinostat and greatest toxicity with panobinostat. Following the addition of HDACi in vitro, there were no changes in markers of T-cell activation or expression of the HIV coreceptors chemokine (C-X-C motif) receptor 4 (CXCR4) or chemokine (C-C motif) receptor type 5 (CCR5). ChIP analysis of latently infected CCL19-treated primary CD4 T cells showed binding by HDAC1, HDAC2 and HDAC3 to the LTR with removal of HDAC1 and HDAC2 following treatment with the HDACi vorinostat and HDAC1 only following treatment with entinostat. Conclusion: The HDACi entinostat, selective for inhibition of class I HDACs, induced virus expression in latently infected primary CD4 T cells making this compound an attractive novel option for future clinical trials. ? 2013 Wolters Kluwer Health Lippincott Williams Wilkins.

AB - Objectives: To compare the potency, toxicity and mechanism of action of multiple histone deacetylase inhibitors (HDACi) in activating HIV production from latency. Design: In-vitro analysis of HDACi in a primary T-cell model of HIV latency and latently infected cell lines. Methods: Latently infected chemokine ligand 19 (CCL19)-treated CD4 T cells and the latently infected cell lines ACH2 and J-Lat were treated with a panel of HDACi, including entinostat, vorinostat, panonbinostat and MCT3. Viral production and cell viability were compared. Expression of cellular HDACs was measured by western blot and PCR. Association of HDACs with the HIV long-terminal repeat (LTR) using latently infected CCL19-treated primary CD4 T cells in the presence and absence of specific HDACi was determined by chromatin immunoprecipitation (ChIP). Results: We demonstrated considerable variation in the potency and toxicity of HDACi in latently infected primary CD4 T cells and cell lines. All HDACi tested activated HIV production in latently infected primary T cells with greatest potency demonstrated with entinostat and vorinostat and greatest toxicity with panobinostat. Following the addition of HDACi in vitro, there were no changes in markers of T-cell activation or expression of the HIV coreceptors chemokine (C-X-C motif) receptor 4 (CXCR4) or chemokine (C-C motif) receptor type 5 (CCR5). ChIP analysis of latently infected CCL19-treated primary CD4 T cells showed binding by HDAC1, HDAC2 and HDAC3 to the LTR with removal of HDAC1 and HDAC2 following treatment with the HDACi vorinostat and HDAC1 only following treatment with entinostat. Conclusion: The HDACi entinostat, selective for inhibition of class I HDACs, induced virus expression in latently infected primary CD4 T cells making this compound an attractive novel option for future clinical trials. ? 2013 Wolters Kluwer Health Lippincott Williams Wilkins.

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DO - 10.1097/QAD.0000000000000067

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