Abstract
HIV-1 latency allows the virus to persist until reactivation, in a transcriptionally silent form in its cellular reservoirs despite the presence of effective cART. Such viral persistence represents a major barrier to HIV eradication since treatment interruption leads to rebound plasma viremia. Polycomb group (PcG) proteins have recently got a considerable attention in regulating HIV-1 post-integration latency as they are involved in the repression of proviral gene expression through the methylation of histones. This epigenetic regulation plays an important role in the establishment and maintenance of HIV-1 latency. In fact, PcG proteins act in complexes and modulate the epigenetic signatures of integrated HIV-1 promoter. Key role played by PcG proteins in the molecular control of HIV-1 latency has led to hypothesize that PcG proteins may represent a valuable target for future HIV-1 therapy in purging HIV-1 reservoirs. In this regard, various small molecules have been synthesized or explored to specifically block the epigenetic activity of PcG. In this review, we will highlight the possible therapeutic approaches to achieve either a functional or sterilizing cure of HIV-1 infection with special focus on histone methylation by PcG proteins together with current and novel pharmacological approaches to reactivate HIV-1 from latency that could ultimately lead towards a better clearance of viral latent reservoirs.
Highlights
Over the last two decades, combination antiretroviral therapy has dramatically improved the management of human immunodeficiency virus type 1 (HIV-1) infection and remarkably declined the morbidity and mortality associated with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) [1]
enhancer of zeste homolog 2 (EZH2) inhibitor 3-deazaneplanocin A (DZNep) significantly reactivates HIV-1 latent reservoirs while the selective inhibitors of suppressor of variegation 3-9 homolog 1 (Suv39h1) and G9a have modest effect on HIV-1 latency. These findings have suggested that histone methyltransferase inhibitors (HMTIs) EZH2 inhibitors could represent an attractive and promising therapeutic drug target in the eradication of HIV-1 latent reservoirs [79, 80]
These two compounds are different from other EZH2 inhibitors by exhibiting new molecular structure. Their activities are very low (IC50 values of 22.6 and 10.3 μmole/ L, respectively) and require further optimization [177]. These findings clearly indicate that Polycomb group (PcG) proteins are associated with maintenance of HIV-1 latency (Table 2)
Summary
Over the last two decades, combination antiretroviral therapy (cART) has dramatically improved the management of human immunodeficiency virus type 1 (HIV-1) infection and remarkably declined the morbidity and mortality associated with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) [1]. Enhancer of Zeste 2 Enhancer of Zeste homolog 2 (EZH2) is a member of PRC2 that contains histone methyltransferase activities, and it acts as an epigenetic regulator with critical consequences of promoting HIV-1 gene silencing.
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