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 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.
Gilead Sciences, Foster City, California, United States of America.
Datsen George
DG
Wei
Gilead Sciences, Foster City, California, United States of America.
Vicki
V
Chiang
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Elizabeth
E
Fyne
Gilead Sciences, Foster City, California, United States of America.
Mini
M
Balakrishnan
Gilead Sciences, Foster City, California, United States of America.
Tiffany
T
Barnes
Gilead Sciences, Foster City, California, United States of America.
Michael
M
Graupe
Gilead Sciences, Foster City, California, United States of America.
Joseph
J
Hesselgesser
Gilead Sciences, Foster City, California, United States of America.
Alivelu
A
Irrinki
Gilead Sciences, Foster City, California, United States of America.
Jeffrey P
JP
Murry
Gilead Sciences, Foster City, California, United States of America.
George
G
Stepan
Gilead Sciences, Foster City, California, United States of America.
Kirsten M
KM
Stray
Gilead Sciences, Foster City, California, United States of America.
Angela
A
Tsai
Gilead Sciences, Foster City, California, United States of America.
Helen
H
Yu
HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
Jonathan
J
Spindler
HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
Mary
M
Kearney
Department of Pathology, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
Celsa A
CA
Spina
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Deborah
D
McMahon
Quest Clinical Research, San Francisco, California, United States of America.
Jacob
J
Lalezari
Gilead Sciences, Foster City, California, United States of America.
Derek
D
Sloan
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
John
J
Mellors
Gilead Sciences, Foster City, California, United States of America.
Romas
R
Geleziunas
Gilead Sciences, Foster City, California, United States of America.
Tomas
T
Cihlar
D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D002478:Cells, Cultured; D047630:Depsipeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*
D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; C087123:romidepsin; D006655:Histone Deacetylases