Editorial: JQ1: giving HIV-1 expression a boost by blocking bromodomains?

In infected individuals, HIV-1 causes a decline in CD4 T cells, which is the etiological cause of the characteristic immunodeficiency seen in patients with AIDS. Although most infected CD4 T cells appear to die quickly (t1/2 1 day), a small but significant number of infected cells are not killed. Instead, they revert to a quiescent state, turn off HIV-1 gene expression, and persist as long-lived memory T cells carrying latent HIV-1 genomes. The frequency of resting CD4 T cells that carry HIV-1 genomes is 100 in 10. These cells comprise a library, called the latent reservoir, of previously circulating HIV-1 variants [1–3]. As a result of the extreme stability of this reservoir, individuals infected with HIV-1 must undergo lifelong treatment with HAART [4]. Adherence to drug regimens is critical for controlling viremia, and treatment interruptions can lead to rapid viral rebound, even though only 1% of the viral library consists of a replicationcompetent virus. Compared with earlier treatment regimens, the currently available antiretroviral drugs cause far fewer side effects and allow easier dosing in the form of combination pills. As a result, infected individuals can expect a higher quality of life with a near-normal life expectancy if treatment is started early and adherence is good. Still, there are patients for whom adherence is difficult due to circumstance, cost, or accessibility. In addition, the potential adverse effects of life-long HAART are, as yet, unknown. There is great impetus in the field, consequently, to find a cure, and much research is dedicated to eradication of the latent reservoir—the single greatest barrier to curing HIV-1 infection. Unfortunately, latently infected cells are effectively indistinguishable from uninfected cells. Therefore, to purge the latent reservoir, all CD4 T cells that harbor replication-competent proviruses would have to be activated and then killed, either by viral cytopathic effects or immune effector mechanisms. Recent findings have shown that cytolytic T lymphocyte responses can be boosted with HIV-1-specific antigens to more efficiently kill infected cells, in which latency has been reversed [5]. Thus, the arguably larger challenge lies in activating only those cells containing a provirus, as global activation of CD4 T cells could trigger a fatal systemic immune response. There were early attempts to purge the latent reservoir and improve clinical outcomes by adding intermittent IL-2 to the treatment regimen of patients on HAART [6]; however, a rapid rebound in viremia occurred after treatment was interrupted [7]. In the years following, a connection emerged, linking the transcriptional activation of HIV-1 and the chromatin state of the LTR, which serves as the HIV-1 promoter [8, 9]. Notably, studies of the acetylation of HIV-1 Tat and of histones positioned at the LTR led to the discovery that HDAC inhibitors can strongly affect viral gene expression. Several drugs that target acetylation have been shown to reactivate latent HIV-1. Among these are trichostatin A, sodium valproate, and SAHA (Vorinostat), which are all HDAC inhibitors. Sodium valproate and SAHA have been tested in preliminary clinical trials (for review, see ref. [10]). 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. This drug was developed originally as an antiproliferative and functions by binding to bromodomains [12], which are found in many well-studied acetyltransferases, such as p300 and p300/CREB-binding protein-associated factor, and interact specifically with acetylated lysines. JQ1 was discovered in a high-throughput screen of synthesized compounds that were predicted to fit into a central hydrophobic cavity shared by many bromodomains. To test the inhibitory effect of JQ1, a particular bromodomain-containing protein, Brd4, was used as a result of its possible role in NUT midline carcinoma and because it exhibited the highest binding specificity for JQ1 in its bromodomain protein family. Brd4 can decipher the histone code through interaction with acetylated histone tails [13]. As such, in the original study that characterized JQ1, addition of the compound to Brd4-dependent cell lines resulted in antiproliferative effects by displacing a Brd4 fusion oncoprotein from chromatin. In concert with its interaction with histones, Brd4 also acts as a bridge between the mediator complex and P-TEFb, thereby recruiting P-TEFb to generic cellular promoters (Fig. 1) [14, 15]. P-TEFb is a heterodimer composed