Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing.

Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we...

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Autores principales:	Datsen George Wei, Vicki Chiang, Elizabeth Fyne, Mini Balakrishnan, Tiffany Barnes, Michael Graupe, Joseph Hesselgesser, Alivelu Irrinki, Jeffrey P Murry, George Stepan, Kirsten M Stray, Angela Tsai, Helen Yu, Jonathan Spindler, Mary Kearney, Celsa A Spina, Deborah McMahon, Jacob Lalezari, Derek Sloan, John Mellors, Romas Geleziunas, Tomas Cihlar
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/ac65303f63b846a6ab208ba464922569
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spelling	oai:doaj.org-article:ac65303f63b846a6ab208ba4649225692021-11-18T06:06:43ZHistone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing.1553-73661553-737410.1371/journal.ppat.1004071https://doaj.org/article/ac65303f63b846a6ab208ba4649225692014-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24722454/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD), a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC50 = 4.5 nM) compared with vorinostat (VOR; EC50 = 3,950 nM) and other histone deacetylase (HDAC) inhibitors in clinical development including panobinostat (PNB; EC50 = 10 nM). The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART), a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 µM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART.Datsen George WeiVicki ChiangElizabeth FyneMini BalakrishnanTiffany BarnesMichael GraupeJoseph HesselgesserAlivelu IrrinkiJeffrey P MurryGeorge StepanKirsten M StrayAngela TsaiHelen YuJonathan SpindlerMary KearneyCelsa A SpinaDeborah McMahonJacob LalezariDerek SloanJohn MellorsRomas GeleziunasTomas CihlarPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 10, Iss 4, p e1004071 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Datsen George Wei Vicki Chiang Elizabeth Fyne Mini Balakrishnan Tiffany Barnes Michael Graupe Joseph Hesselgesser Alivelu Irrinki Jeffrey P Murry George Stepan Kirsten M Stray Angela Tsai Helen Yu Jonathan Spindler Mary Kearney Celsa A Spina Deborah McMahon Jacob Lalezari Derek Sloan John Mellors Romas Geleziunas Tomas Cihlar Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing.
description	Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD), a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC50 = 4.5 nM) compared with vorinostat (VOR; EC50 = 3,950 nM) and other histone deacetylase (HDAC) inhibitors in clinical development including panobinostat (PNB; EC50 = 10 nM). The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART), a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 µM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART.
format	article
author	Datsen George Wei Vicki Chiang Elizabeth Fyne Mini Balakrishnan Tiffany Barnes Michael Graupe Joseph Hesselgesser Alivelu Irrinki Jeffrey P Murry George Stepan Kirsten M Stray Angela Tsai Helen Yu Jonathan Spindler Mary Kearney Celsa A Spina Deborah McMahon Jacob Lalezari Derek Sloan John Mellors Romas Geleziunas Tomas Cihlar
author_facet	Datsen George Wei Vicki Chiang Elizabeth Fyne Mini Balakrishnan Tiffany Barnes Michael Graupe Joseph Hesselgesser Alivelu Irrinki Jeffrey P Murry George Stepan Kirsten M Stray Angela Tsai Helen Yu Jonathan Spindler Mary Kearney Celsa A Spina Deborah McMahon Jacob Lalezari Derek Sloan John Mellors Romas Geleziunas Tomas Cihlar
author_sort	Datsen George Wei
title	Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing.
title_short	Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing.
title_full	Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing.
title_fullStr	Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing.
title_full_unstemmed	Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing.
title_sort	histone deacetylase inhibitor romidepsin induces hiv expression in cd4 t cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/ac65303f63b846a6ab208ba464922569
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Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing.

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