histamine-1 receptor antagonist br Author contributions br C

Author contributions
Conflict of interest
Acknowledgments
Introduction The use of fully suppressive combination Anti-Retroviral Therapy (c-ART), aside from efficiently inhibiting viral replication, has provided important insights into the characteristics and dynamics of the persistent latent pool of the HIV-1 virus in infected patients (Pierson et al., 2000; Dahabieh et al., 2015; Geeraert et al., 2008; Chun et al., 1995, 2007). Studies have led to the identification of quiescent latently infected CD4+ memory T cells, which harbor latent HIV-1, as the major barrier to a cure (Finzi et al., 1999; Siliciano et al., 2003). The majority of HIV-1 infected patients are diagnosed during the chronic phase of the infection, when a large reservoir of latently infected histamine-1 receptor antagonist is already established (Strain et al., 2005; Watanabe et al., 2011; Whitney et al., 2014). Therefore, to achieve a functional cure, recent pharmacological efforts have centered on targeting the reservoir harboring latent HIV-1 for activation in order to induce viral replication. As a second step, following latency reversal, the infected cells would be exposed to viral cytopathic effects and the immune system, thereby eliminating or depleting the infected cells that constitute the latent reservoir (Deeks, 2012). Latently HIV-1 infected cells harbor replication competent HIV-1 virus, whose gene expression is transcriptionally blocked. Once integrated, the double stranded HIV-1 provirus behaves as a cellular gene and becomes subject to a complex network of molecular mechanisms that determine its transcriptional state (Mbonye and Karn, 2014; Mahmoudi, 2012; Dahabieh et al., 2015). As part of the genome, the HIV-1 chromatin structure at the 5′ LTR, the HIV-1 promoter, is highly organized into specifically deposited nucleosomes: in its latent state, the 5\'LTR is organized into nuc-0 and nuc-1, two strictly positioned nucleosomes that are separated by DHS1, a region sensitive to nuclease digestion, which encompasses a loosely positioned nucleosome (Verdin, 1991; Verdin and Van Lint, 1995; Rafati et al., 2011). The positioning of nuc-1, downstream of the core promoter transcription start site, is the hallmark of the repressed 5′ LTR. Upon activation, nuc-1 becomes rapidly and specifically disrupted, allowing for HIV-1 gene expression to occur (Verdin and Van Lint, 1995; Verdin et al., 1993; Van Lint et al., 1996; Rafati et al., 2011). The chromatin structure of the HIV-1 promoter, as with cellular promoters, is generated through the concerted activity of protein complexes, which remodel chromatin (Mbonye and Karn, 2014; Lusic and Giacca, 2015). This is in part accomplished by loosening or tightening histone-DNA interaction via posttranslational modifications on histone tails, which include acetylation and methylation (Zentner and Henikoff, 2013). Of particular interest for regulation of HIV-1 transcription, histone deacetylases have been shown to play a critical role in repressing gene expression at the HIV-1 LTR (Van Lint et al., 1996; Keedy et al., 2009; Marban et al., 2007; Williams et al., 2006; Barton and Margolis, 2013; Barton et al., 2014; Lu et al., 2014) and represent an important target for therapies aimed at activation of latent virus or latency reversal. Accordingly, a number of small molecule HDAC inhibitors including valproic acid (Edelstein et al., 2009), suberoylanilide hydroxamic acid (SAHA) (Contreras et al., 2009), Panobinostat (Rasmussen et al., 2013), and Romidepsin (Wei et al., 2014) have been or are currently under clinical investigation for their potential in therapeutic HIV-1 latency reversal (Archin et al., 2012, 2014; Elliott et al., 2014; Barton et al., 2015; Rasmussen et al., 2014). Initial data from preclinical and clinical studies using HDAC inhibitors in therapeutic latency reversal suggest that while promising, HDAC inhibitors alone may not be sufficient in activation of the latent HIV-1 to the extent required to accomplish clinically significant depletion of the latent reservoir in patients. HIV-1 transcriptional latency is a complex molecular phenomenon, driven and controlled by multiple mechanisms, including the position of virus integration in the genome, its orientation and proximity to endogenous genes, and the presence and activity of host transcription factors and cofactors on the HIV-1 promoter (Van Lint et al., 2013; Dahabieh et al., 2015; Mbonye and Karn, 2014; Ruelas and Greene, 2013; Matsuda et al., 2015). Therefore, the specific transcriptional environment of each latently infected cell is likely to impact its responsiveness to activating molecules. Accordingly, the molecular mechanisms at play in transcriptionally silencing the latent reservoir are likely to be diverse and heterogeneous. Indeed, data obtained from in vitro models using latently infected cell lines support the notion that targeting two or more pathways in combination is more effective in activating latent HIV-1 by inducing synergistic activation of the latent promoter (De Crignis and Mahmoudi, 2014; Laird et al., 2015). It is therefore critical to identify and target multiple molecular effectors with distinct mechanisms that drive HIV-1 latency in order to obtain more effective and synergistic activation of the latent reservoir.