Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation
Thomas Aagaard Rasmussen, Ole Schmeltz Søgaard, Christel Brinkmann, Fiona Wightman, Sharon R Lewin, Jesper Melchjorsen, Charles Dinarello, Lars Østergaard, Martin Tolstrup, Thomas Aagaard Rasmussen, Ole Schmeltz Søgaard, Christel Brinkmann, Fiona Wightman, Sharon R Lewin, Jesper Melchjorsen, Charles Dinarello, Lars Østergaard, Martin Tolstrup
Abstract
Objective: We aimed to compare the potential for inducing HIV production and the effect on T-cell activation of potent HDAC inhibitors undergoing clinical investigation.
Design: In vitro study
Results: The various HDAC inhibitors displayed significant potency differences in stimulating HIV-1 expression from the latently infected cell lines with panobinostat>givinostat ≈belinostat>vorinostat>valproic acid. Panobinostat was significantly more potent than all other HDAC inhibitors and induced virus production even in the very low concentration range 8-31 nM. The proportion of primary T-cells expressing the early activation marker CD69 increased moderately in all HDAC inhibitor-treated cells compared with untreated cells. Finally, proof was obtained that panobinostat, givinostat and belinostat induce virus production in latently infected primary cells at therapeutic concentrations with panobinostat being the most potent stimulator.
Methods: The latently infected cell lines ACH2 and U1 were treated with the HDAC inhibitors panobinostat, givinostat, belinostat, vorinostat and valproic acid. Viral induction was estimated by p24 production. Peripheral blood mononuclear cells from uninfected donors were treated with the HDAC inhibitors and the expression of activation markers on T-cell phenotypes was measured using flow cytometry. Finally, the ability of givinostat, belinostat and panobinostat to reactivate latent HIV-1 expression in primary T-cells was investigated employing a CCL19-induced latent primary CD4+ T cell infection model.
Conclusion: At therapeutic concentrations panobinostat stimulate HIV-1 expression in latently infected cells with greater potency than other HDAC inhibitors undergoing clinical investigation. These findings warrant further investigation and panobinostat is now being advanced into clinical testing against latent HIV infection.
Keywords: HIV; HIV cure; HIV eradication; histone deacetylase inhibitors.
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References
- Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009;15:893–900. doi: 10.1038/nm.1972.
- Chun TW, Finzi D, Margolick J, Chadwick K, Schwartz D, Siliciano RF. In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nat Med. 1995;1:1284–90. doi: 10.1038/nm1295-1284.
- Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, Baseler M, et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 1997;94:13193–7. doi: 10.1073/pnas.94.24.13193.
- Archin NM, Espeseth A, Parker D, Cheema M, Hazuda D, Margolis DM. Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid. AIDS Res Hum Retroviruses. 2009;25:207–12. doi: 10.1089/aid.2008.0191.
- Shan L, Deng K, Shroff NS, Durand CM, Rabi SA, Yang HC, et al. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity. 2012;36:491–501. doi: 10.1016/j.immuni.2012.01.014.
- Van Lint C, Emiliani S, Ott M, Verdin E. Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation. EMBO J. 1996;15:1112–20.
- Coull JJ, Romerio F, Sun JM, Volker JL, Galvin KM, Davie JR, et al. The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1. J Virol. 2000;74:6790–9. doi: 10.1128/JVI.74.15.6790-6799.2000.
- Williams SA, Chen LF, Kwon H, Ruiz-Jarabo CM, Verdin E, Greene WC. NF-kappaB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation. EMBO J. 2006;25:139–49. doi: 10.1038/sj.emboj.7600900.
- Imai K, Okamoto T. Transcriptional repression of human immunodeficiency virus type 1 by AP-4. J Biol Chem. 2006;281:12495–505. doi: 10.1074/jbc.M511773200.
- Jiang G, Espeseth A, Hazuda DJ, Margolis DM. c-Myc and Sp1 contribute to proviral latency by recruiting histone deacetylase 1 to the human immunodeficiency virus type 1 promoter. J Virol. 2007;81:10914–23. doi: 10.1128/JVI.01208-07.
- Lusic M, Marcello A, Cereseto A, Giacca M. Regulation of HIV-1 gene expression by histone acetylation and factor recruitment at the LTR promoter. EMBO J. 2003;22:6550–61. doi: 10.1093/emboj/cdg631.
- Tyagi M, Karn J. CBF-1 promotes transcriptional silencing during the establishment of HIV-1 latency. EMBO J. 2007;26:4985–95. doi: 10.1038/sj.emboj.7601928.
- Contreras X, Schweneker M, Chen CS, McCune JM, Deeks SG, Martin J, et al. Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells. J Biol Chem. 2009;284:6782–9. doi: 10.1074/jbc.M807898200.
- Matalon S, Palmer BE, Nold MF, Furlan A, Kassu A, Fossati G, et al. The histone deacetylase inhibitor ITF2357 decreases surface CXCR4 and CCR5 expression on CD4(+) T-cells and monocytes and is superior to valproic acid for latent HIV-1 expression in vitro. J Acquir Immune Defic Syndr. 2010;54:1–9. doi: 10.1097/QAI.0b013e3181d3dca3.
- Reuse S, Calao M, Kabeya K, Guiguen A, Gatot JS, Quivy V, et al. Synergistic activation of HIV-1 expression by deacetylase inhibitors and prostratin: implications for treatment of latent infection. PLoS One. 2009;4:e6093. doi: 10.1371/journal.pone.0006093.
- Choi BS, Lee HS, Oh YT, Hyun YL, Ro S, Kim SS, et al. Novel histone deacetylase inhibitors CG05 and CG06 effectively reactivate latently infected HIV-1. AIDS. 2010;24:609–11. doi: 10.1097/QAD.0b013e328333bfa1.
- Ylisastigui L, Archin NM, Lehrman G, Bosch RJ, Margolis DM. Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression. AIDS. 2004;18:1101–8. doi: 10.1097/00002030-200405210-00003.
- Yin H, Zhang Y, Zhou X, Zhu H. Histonedeacetylase inhibitor Oxamflatin increase HIV-1 transcription by inducing histone modification in latently infected cells. Mol Biol Rep. 2011;38:5071–8. doi: 10.1007/s11033-010-0653-6.
- Wightman F, Ellenberg P, Churchill M, Lewin SR. HDAC inhibitors in HIV. Immunol Cell Biol. 2012;90:47–54. doi: 10.1038/icb.2011.95.
- Matalon S, Rasmussen TA, Dinarello CA. Histone deacetylase inhibitors for purging HIV-1 from the latent reservoir. Mol Med. 2011;17:466–72. doi: 10.2119/molmed.2011.00076.
- Lehrman G, Hogue IB, Palmer S, Jennings C, Spina CA, Wiegand A, et al. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet. 2005;366:549–55. doi: 10.1016/S0140-6736(05)67098-5.
- Archin NM, Cheema M, Parker D, Wiegand A, Bosch RJ, Coffin JM, et al. Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection. PLoS One. 2010;5:e9390. doi: 10.1371/journal.pone.0009390.
- Archin NM, Eron JJ, Palmer S, Hartmann-Duff A, Martinson JA, Wiegand A, et al. Valproic acid without intensified antiviral therapy has limited impact on persistent HIV infection of resting CD4+ T cells. AIDS. 2008;22:1131–5. doi: 10.1097/QAD.0b013e3282fd6df4.
- Routy JP, Tremblay CL, Angel JB, Trottier B, Rouleau D, Baril JG, et al. Valproic acid in association with highly active antiretroviral therapy for reducing systemic HIV-1 reservoirs: results from a multicentre randomized clinical study. HIV Med. 2012;13:291–6. doi: 10.1111/j.1468-1293.2011.00975.x.
- Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012;487:482–5. doi: 10.1038/nature11286.
- Furlan A, Monzani V, Reznikov LL, Leoni F, Fossati G, Modena D, et al. Pharmacokinetics, safety and inducible cytokine responses during a phase 1 trial of the oral histone deacetylase inhibitor ITF2357 (givinostat) Mol Med. 2011;17:353–62. doi: 10.2119/molmed.2011.00020.
- Vojinovic J, Dinarello CA, Damjano N, Oldoni T. Safety and Efficacy of Oral ITF2357 in Patients with Active Systemic Onset Juvenile Idiopathic Arthritis (SOJIA) - Results of a Phase II, Open Label, International, Multicentre Clinical Trial. Abstract 2008 Annual Scientific Meeting, American College of Rheumatology 2008.
- Rathkopf D, Wong BY, Ross RW, Anand A, Tanaka E, Woo MM, et al. A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer. Cancer Chemother Pharmacol. 2010;66:181–9. doi: 10.1007/s00280-010-1289-x.
- Dickinson M, Ritchie D, DeAngelo DJ, Spencer A, Ottmann OG, Fischer T, et al. Preliminary evidence of disease response to the pan deacetylase inhibitor panobinostat (LBH589) in refractory Hodgkin Lymphoma. Br J Haematol. 2009;147:97–101. doi: 10.1111/j.1365-2141.2009.07837.x.
- Ellis L, Pan Y, Smyth GK, George DJ, McCormack C, Williams-Truax R, et al. Histone deacetylase inhibitor panobinostat induces clinical responses with associated alterations in gene expression profiles in cutaneous T-cell lymphoma. Clin Cancer Res. 2008;14:4500–10. doi: 10.1158/1078-0432.CCR-07-4262.
- Prince HM, Bishton MJ, Harrison SJ. Clinical studies of histone deacetylase inhibitors. Clin Cancer Res. 2009;15:3958–69. doi: 10.1158/1078-0432.CCR-08-2785.
- Prince HM, Bishton MJ, Johnstone RW. Panobinostat (LBH589): a potent pan-deacetylase inhibitor with promising activity against hematologic and solid tumors. Future Oncol. 2009;5:601–12. doi: 10.2217/fon.09.36.
- Wightman F, Ramanayake S, Saleh S, Solomon A, Dear A, Shebu-Xhilaga M, et al. Potency and Toxicity of HDACi and Other Immune Activators in Inducing HIV Production Using a Primary Resting T Cell Model of HIV Latency. Conference on Retroviruses and Opportunistic Infections. Boston, 2011.
- Blazkova J, Chun TW, Belay BW, Murray D, Justement JS, Funk EK, et al. Effect of histone deacetylase inhibitors on HIV production in latently infected, resting CD4(+) T cells from infected individuals receiving effective antiretroviral therapy. J Infect Dis. 2012;206:765–9. doi: 10.1093/infdis/jis412.
- Leoni F, Fossati G, Lewis EC, Lee JK, Porro G, Pagani P, et al. The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol Med. 2005;11:1–15. doi: 10.2119/2006-00005.Dinarello.
- Heredia A, Gilliam B, DeVico A, Le N, Bamba D, Flinko R, et al. CCR5 density levels on primary CD4 T cells impact the replication and Enfuvirtide susceptibility of R5 HIV-1. AIDS. 2007;21:1317–22. doi: 10.1097/QAD.0b013e32815278ea.
- Steele NL, Plumb JA, Vidal L, Tjørnelund J, Knoblauch P, Buhl-Jensen P, et al. Pharmacokinetic and pharmacodynamic properties of an oral formulation of the histone deacetylase inhibitor Belinostat (PXD101) Cancer Chemother Pharmacol. 2011;67:1273–9. doi: 10.1007/s00280-010-1419-5.
- Maiso P, Carvajal-Vergara X, Ocio EM, López-Pérez R, Mateo G, Gutiérrez N, et al. The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance. Cancer Res. 2006;66:5781–9. doi: 10.1158/0008-5472.CAN-05-4186.
- Lewin SR, Rouzioux C. HIV cure and eradication: how will we get from the laboratory to effective clinical trials? AIDS. 2011;25:885–97. doi: 10.1097/QAD.0b013e3283467041.
- Vo DD, Prins RM, Begley JL, Donahue TR, Morris LF, Bruhn KW, et al. Enhanced antitumor activity induced by adoptive T-cell transfer and adjunctive use of the histone deacetylase inhibitor LAQ824. Cancer Res. 2009;69:8693–9. doi: 10.1158/0008-5472.CAN-09-1456.
- Beliakova-Bethell N, Zhang JX, Singhania A, Lee V, Terry VH, Richman DD, et al. Suberoylanilide hydroxamic acid induces limited changes in the transcriptome of primary CD4(+) T cells. AIDS. 2013;27:29–37. doi: 10.1097/QAD.0b013e32835b3e26.
- van Praag RM, Prins JM, Roos MT, Schellekens PT, Ten Berge IJ, Yong SL, et al. OKT3 and IL-2 treatment for purging of the latent HIV-1 reservoir in vivo results in selective long-lasting CD4+ T cell depletion. J Clin Immunol. 2001;21:218–26. doi: 10.1023/A:1011091300321.
- Akimova T, Beier UH, Liu Y, Wang L, Hancock WW. Histone/protein deacetylases and T-cell immune responses. Blood. 2012;119:2443–51. doi: 10.1182/blood-2011-10-292003.
- Song W, Tai YT, Tian Z, Hideshima T, Chauhan D, Nanjappa P, et al. HDAC inhibition by LBH589 affects the phenotype and function of human myeloid dendritic cells. Leukemia. 2011;25:161–8. doi: 10.1038/leu.2010.244.
- Krowka JF, Cuevas B, Maron DC, Steimer KS, Ascher MS, Sheppard HW. Expression of CD69 after in vitro stimulation: a rapid method for quantitating impaired lymphocyte responses in HIV-infected individuals. J Acquir Immune Defic Syndr Hum Retrovirol. 1996;11:95–104. doi: 10.1097/00042560-199601010-00013.
- Dinarello CA, Fossati G, Mascagni P. Histone deacetylase inhibitors for treating a spectrum of diseases not related to cancer. Mol Med. 2011;17:333–52. doi: 10.2119/molmed.2011.00116.
- Grabiec AM, Tak PP, Reedquist KA. Function of histone deacetylase inhibitors in inflammation. Crit Rev Immunol. 2011;31:233–63. doi: 10.1615/CritRevImmunol.v31.i3.40.
- Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006;5:769–84. doi: 10.1038/nrd2133.
- Shehu-Xhilaga M, Rhodes D, Wightman F, Liu HB, Solomon A, Saleh S, et al. The novel histone deacetylase inhibitors metacept-1 and metacept-3 potently increase HIV-1 transcription in latently infected cells. AIDS. 2009;23:2047–50. doi: 10.1097/QAD.0b013e328330342c.
- Keedy KS, Archin NM, Gates AT, Espeseth A, Hazuda DJ, Margolis DM. A limited group of class I histone deacetylases acts to repress human immunodeficiency virus type 1 expression. J Virol. 2009;83:4749–56. doi: 10.1128/JVI.02585-08.
- Saleh S, Solomon A, Wightman F, Xhilaga M, Cameron PU, Lewin SR. CCR7 ligands CCL19 and CCL21 increase permissiveness of resting memory CD4+ T cells to HIV-1 infection: a novel model of HIV-1 latency. Blood. 2007;110:4161–4. doi: 10.1182/blood-2007-06-097907.
- Saleh S, Wightman F, Ramanayake S, Alexander M, Kumar N, Khoury G, et al. Expression and reactivation of HIV in a chemokine induced model of HIV latency in primary resting CD4+ T cells. Retrovirology. 2011;8:80. doi: 10.1186/1742-4690-8-80.
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