Epigenetic regulation of HIV-1 latency: focus on polycomb group (PcG) proteins

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.

TRIM28 promotes HIV-1 latency by SUMOylating CDK9 and inhibiting P-TEFb

“…We found that many proteins restricted the activity of HIV-1 promoter based on the expression level of luciferase upon knockdown each target (Figure 1A). The top hit proteins included HP1α, GLP, SUZ12 and CYLD, which have been identified to inhibit HIV-1 transcription (Ding et al, 2013; Khan et al, 2018; Manganaro et al, 2014). Intriguingly, we found that knockdown of two less-defined SUMOylation pathway genes TRIM28 and SUMO4 significantly upregulated HIV-1 promoter activity (Figure 1A, Figure 1—figure supplement 1A–B).…”

Development of Direct-acting Antiviral and Host-targeting Agents for Treatment of Hepatitis B Virus Infection

“…The small molecule C646 also achieves this effect, by specifically inhibiting p300 and CBP histone acetyltransferases 63 . Drugs that modify epigenetic regulation have also been developed to treat patients with cancer or viral infections 64–66 . These agents might be used to inactivate cccDNA in infected hepatocytes.…”

Control of viral infections by epigenetic-targeted therapy

“…Interestingly, the integrated provirus in those cells is subjected to transcriptional silencing by host chromatin-modifying enzymes, comprising deacetylases, methyltransferases, and others [19]. This paved the road to the emergence of two new epigenetic therapeutic approaches, namely the “shock and kill” and the “block and lock” strategies [20–23]. Here, we present general points about these two anti-HIV therapeutic strategies (Fig.…”