Abstract
Despite combination antiretroviral therapy (cART), acquired immunodeficiency syndrome (AIDS), predominantly caused by the human immunodeficiency virus type 1 (HIV-1), remains incurable. The barrier to a cure lies in the virus' ability to establish a latent infection in HIV/AIDS patients. Unsurprisingly, efforts for a sterilizing cure have focused on the “shock and kill” strategy using latency-reversing agents (LRAs) to complement cART in order to eliminate these latent reservoirs. However, this method faces numerous challenges. Recently, the “block and lock” strategy has been proposed. It aims to reinforce a deep state of latency and prevent sporadic reactivation (“blip”) of HIV-1 using latency-promoting agents (LPAs) for a functional cure. Our studies of curaxin 100 (CBL0100), a small-molecule targeting the facilitates chromatin transcription (FACT) complex, show that it blocks both HIV-1 replication and reactivation in in vitro and ex vivo models of HIV-1. Mechanistic investigation elucidated that CBL0100 preferentially targets HIV-1 transcriptional elongation and decreases the occupancy of RNA Polymerase II (Pol II) and FACT at the HIV-1 promoter region. In conclusion, CBL0100 is a newly identified inhibitor of HIV-1 transcription that can be used as an LPA in the “block and lock” cure strategy.
Highlights
The increase availability of combination antiretroviral therapy has significantly reduced human immunodeficiency virus type 1 (HIV-1) associated morbidity and mortality (Deeks and Phillips, 2009; Ruelas and Greene, 2013)
Several groups including ours recognized that the facilitates chromatin transcription (FACT) complex is an important host factor that plays a role in regulating HIV-1 acute infection, as well as HIV-1 latency (Huang et al, 2015; Lopez et al, 2016)
Small molecule compounds, target the activity of the FACT complex, and elicit an antitumor activity (Gasparian et al, 2011). Given these earlier studies our primary goal was to investigate whether curaxins possess antiretroviral activity through their targeting of the FACT complex
Summary
The increase availability of combination antiretroviral therapy (cART) has significantly reduced HIV-1 associated morbidity and mortality (Deeks and Phillips, 2009; Ruelas and Greene, 2013). CART is still unable to completely eliminate HIV-1 because cART-treated patients cannot clear the latently infected cells, mainly in resting memory CD4+ T cells. These viral reservoirs are long-lived, self-replenishing, and refractory to cART despite lowering plasma viral load to undetectable levels (Chomont et al, 2009; Darcis et al, 2017). These viral reservoirs contribute to residual viremia during cART and viral rebound following cART. Several roadblocks prevent this strategy from being effective (Darcis et al, 2017)
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