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

Wightman, Fionaa,b; Lu, Hao K.a,b; Solomon, Ajantha E.a,b; Saleh, Suhaa,b; Harman, Andrew N.c; Cunningham, Anthony L.c; Gray, Lachlanb,d; Churchill, Melissaa,b; Cameron, Paul U.a,b,e; Dear, Anthony E.f; Lewin, Sharon R.a,b,e

doi: 10.1097/QAD.0000000000000067
Basic Science

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.

aDepartment of Infectious Diseases, Monash University

bCentre for Virology, Burnet Institute, Melbourne, Victoria

cWestmead Millennium Research Institute, Westmead, New South Wales

dDepartment of Biochemistry, Monash University, Clayton

eInfectious Diseases Unit, Alfred Hospital, Melbourne

fAustralian Centre for Blood Diseases, Department of Medicine, Monash University, Melbourne, Victoria, Australia.

Correspondence to Sharon Lewin, Infectious Diseases Unit, Alfred Hospital, Department of Medicine, Monash University, Centre for Virology, Burnet Institute Level 2, Burnet Building Melbourne, VIC, 3004, Australia. E-mail:

Received 29 January, 2013

Revised 05 September, 2013

Accepted 05 September, 2013

© 2013 Lippincott Williams & Wilkins, Inc.