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

Celsa A. Spina¹  John Mellors²  Deborah McMahon²  Elizabeth Fyne²  Kirsten M. Stray³  Mini Balakrishnan³  Joseph Hesselgesser³  Michael Graupe³  Datsen George Wei³  Jeffrey P. Murry³  Alivelu Irrinki³  Helen Yu³  Tomas Cihlar³  Vicki Chiang³  Angela Tsai³  Derek Sloan³  Tiffany Barnes³  Romas Geleziunas³  George Stepan³  Jonathan Spindler⁴  Mary Kearney⁴  Jacob Lalezari⁵ 

[1] Department of Pathology, School of Medicine, University of California San Diego, La Jolla, California, United States of America;Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America;Gilead Sciences, Foster City, California, United States of America;HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America;Quest Clinical Research, San Francisco, California, United States of America

关键词: HIV;    T helper cells;    Memory T cells;    T cells;    HIV infections;    RNA extraction;    Cell cultures;    RNA isolation;   

DOI  :  10.1371/journal.ppat.1004071

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY