BET bromodomain inhibition as a novel strategy for reactivation of HIV-1

Abstract

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.

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“…Brd4 binds P-TEFb through BD II, but JQ1 has a higher affinity for BD I (K d ϳ50 nM for BD I; K d ϳ90 nM for BD II). In the experiments of Banerjee and colleagues [11], experimental concentrations were 500 nM; assuming the cellular drug concentrations were in the same range, it is possible that both BD I and II were occupied by JQ1. Do both bromodomains need to be bound by drug to see the effect?…”

“…In this issue of the Journal of Leukocyte Biology, Banerjee et al [11] examine the effect of a relatively new drug, JQ1, on reactivation of latent HIV-1 in cell culture systems. In contrast to other commonly used latency-reversing agents, JQ1 is not an HDAC inhibitor.…”

Bromodomain and Extra-terminal (BET) Bromodomain Inhibition Activate Transcription via Transient Release of Positive Transcription Elongation Factor b (P-TEFb) from 7SK Small Nuclear Ribonucleoprotein

“…Although JQ1 alone did not reactivate HIV from latently infected primary resting T cells because their levels of P-TEFb are vanishingly low (6,35), JQ1 could become a candidate for combinatorial anti-latency therapy with SAHA and/or other T cell-activating compounds. To this end, during the preparation of this manuscript, Montano and colleagues (36) reported that JQ1 could reactivate minimally latent HIV in , and cell lysates were subjected to immunoprecipitations (IP) with anti-CycT1 (left panels) and anti-BRD4 (right panels) antibodies. The levels of the indicated proteins in the 5% input (right panels) and immunoprecipitations (left panels) were determined by Western blotting (WB).…”

Role of Downstream Elements in Transcriptional Regulation of the HIV-1 Promoter

“…Newer approaches have shown an interest in a novel group of transcriptional regulators that control viral gene expression. These include the bromodomain (BET family) inhibitors that can induce the activation of latent HIV-1 in primary cell models of latency [67][68][69]. Thus, understanding the molecular underpinnings of transcriptional regulation would enhance the progress towards development of a cure for HIV infection.…”