Abstract
While combinatory antiretroviral therapy (cART) can effectively reduce HIV-1 viremia, it cannot eliminate HIV-1 infection. In the presence of cART, viral reservoirs remain latent, impeding the cure of HIV-1/AIDS. Recently, latency-reversing agents (LRAs) have been developed with the intent of purging latent HIV-1, providing an intriguing strategy for the eradication of the residual viral reservoirs. Our earlier studies show that the first-generation, methyl-triazolo bromodomain, and extra-terminal domain inhibitor (BETi), JQ1, facilitates the reversal of HIV-1 latency. BETis have emerged as a new class of compounds that are promising for this HIV-1 “shock and kill” eradication approach. However, when used as a single drug, JQ1 only modestly reverses HIV-1 latency, which complicates studying the underlining mechanisms. Meanwhile, it has been widely discussed that the induction of latent proviruses is stochastic (Ho et al., 2013). Thus, new BETis are currently under active development with focus on improving potency, ease of synthesis and structural diversity. Using fluorous-tagged multicomponent reactions, we developed a novel second-generation, 3,5-dimethylisoxazole BETi based on an imidazo[1,2-a] pyrazine scaffold, UMB-32. Furthermore, we screened 37 UMB-32 derivatives and identified that one, UMB-136, reactivates HIV-1 in multiple cell models of HIV-1 latency with better efficiency than either JQ1 or UMB-32. UMB-136 enhances HIV-1 transcription and increases viral production through the release of P-TEFb. Importantly, UMB-136 enhances the latency-reversing effects of PKC agonists (prostratin, bryostatin-1) in CD8-depleted PBMCs containing latent viral reservoirs. Our results illustrate that structurally improved BETis, such as UMB-136, may be useful as promising LRAs for HIV-1 eradication.
Highlights
The discovery of combinatorial antiretroviral therapy has significantly suppressed human immunodeficiency virus type 1 (HIV-1) infection, and transforming acquired immune deficiency syndrome (AIDS) from an acute lethal disease to a chronic manageable one
A major concern is that when used as a single latency-reversing agents (LRAs), JQ1 fails to efficiently reactivate the latently infected HIV-1 proviruses from most latency cell lines as well as in primary CD4+ T cells (Zhu et al, 2012)
This could be due to that, the latently infected HIV-1 proviruses are insensitive to JQ1 induction or that the HIV-1 latencyreversing effects of LRAs (JQ1) are stochastic which has been widely discussed in the field (Ho et al, 2013)
Summary
The discovery of combinatorial antiretroviral therapy (cART) has significantly suppressed human immunodeficiency virus type 1 (HIV-1) infection, and transforming acquired immune deficiency syndrome (AIDS) from an acute lethal disease to a chronic manageable one. In recent years a strategy to reverse HIV-1 latency using small molecules has been developed; demonstrating the potential to eliminate the viral reservoirs (Choudhary and Margolis, 2011; Rasmussen et al, 2016) These compounds can initiate viral replication, thereby sensitizing the latent reservoir to (i) virally-mediated cytopathic effects and (ii) host immune attack. LRA usage may lead to the provirus becoming insensitive to reactivation, as the HIV-1 latency-reversing effect could be stochastic (Ho et al, 2013) These issues have prompted a need for structurally dissimilar LRAs (ligands as probes of bromodomain function). These early investigations are informative, but they indicate that current BETis require improvement for the use as potent LRAs and that other structurally diversified LRAs are needed to be developed
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