BET bromodomain inhibition as a novel strategy for reactivation of HIV-1.
The persistence of latent HIV-1 remains a major challenge in therapeutic efforts to eradicate infection. We report the capacity for HIV reactivation by a selective small molecule inhibitor of BET family bromodomains, JQ1, a promising therapeutic agent with antioncogenic properties. JQ1 reactivated HIV transcription in models of latent T cell infection and latent monocyte infection. We also tested the effect of exposure to JQ1 to allow recovery of replication-competent HIV from pools of resting CD4(+) T cells isolated from HIV-infected, ART-treated patients. In one of three patients, JQ1 allowed recovery of virus at a frequency above unstimulated conditions. JQ1 potently suppressed T cell proliferation with minimal cytotoxic effect. Transcriptional profiling of T cells with JQ1 showed potent down-regulation of T cell activation genes, including CD3, CD28, and CXCR4, similar to HDAC inhibitors, but JQ1 also showed potent up-regulation of chromatin modification genes, including SIRT1, HDAC6, and multiple lysine demethylases (KDMs). Thus, JQ1 reactivates HIV-1 while suppressing T cell activation genes and up-regulating histone modification genes predicted to favor increased Tat activity. Thus, JQ1 may be useful in studies of potentially novel mechanisms for transcriptional control as well as in translational efforts to identify therapeutic molecules to achieve viral eradication.
Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Camellia
C
Banerjee
Nancie
N
Archin
Daniel
D
Michaels
Anna C
AC
Belkina
Gerald V
GV
Denis
James
J
Bradner
Paola
P
Sebastiani
David M
DM
Margolis
Monty
M
Montano
D001381:Azepines / Q000494:pharmacology* / Q000633:toxicity; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D016000:Cluster Analysis; D005786:Gene Expression Regulation / Q000187:drug effects; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D055017:Monocyte-Macrophage Precursor Cells / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D014158:Transcription, Genetic / Q000187:drug effects; D059467:Transcriptome; D014230:Triazoles / Q000494:pharmacology* / Q000633:toxicity; D014775:Virus Activation / Q000187:drug effects* / Q000235:genetics; D017735:Virus Latency / Q000187:drug effects* / Q000235:genetics
C561695:(+)-JQ1 compound; D001381:Azepines; D014230:Triazoles