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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

Wei, DG and Chiang, V and Fyne, E and Balakrishnan, M and Barnes, T and Graupe, M and Hesselgesser, J and Irrinki, A and Murry, JP and Stepan, G and Stray, KM and Tsai, A and Yu, H and Spindler, J and Kearney, M and Spina, CA and McMahon, D and Lalezari, J and Sloan, D and Mellors, J and Geleziunas, R and Cihlar, T (2014) Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing. PLoS Pathogens, 10 (4). ISSN 1553-7366

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Abstract

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.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Wei, DG
Chiang, V
Fyne, E
Balakrishnan, M
Barnes, T
Graupe, M
Hesselgesser, J
Irrinki, A
Murry, JP
Stepan, G
Stray, KM
Tsai, A
Yu, H
Spindler, J
Kearney, M
Spina, CA
McMahon, Dmcmahond@pitt.eduMCMAHOND
Lalezari, J
Sloan, D
Mellors, Jjwm1@pitt.eduJWM1
Geleziunas, R
Cihlar, T
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorDesrosiers, Ronald C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 January 2014
Date Type: Publication
Journal or Publication Title: PLoS Pathogens
Volume: 10
Number: 4
DOI or Unique Handle: 10.1371/journal.ppat.1004071
Schools and Programs: School of Medicine > Medicine
Refereed: Yes
ISSN: 1553-7366
Date Deposited: 01 Jul 2014 16:32
Last Modified: 29 Jan 2019 15:55
URI: http://d-scholarship.pitt.edu/id/eprint/22129

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