Host Methyltransferases and Demethylases: Potential New Epigenetic Targets for HIV Cure Strategies and Beyond

Abstract

A successful HIV cure strategy may require reversing HIV latency to purge hidden viral reservoirs or enhancing HIV latency to permanently silence HIV transcription. Epigenetic modifying agents show promise as antilatency therapeutics in vitro and ex vivo, but also affect other steps in the viral life cycle. In this review, we summarize what we know about cellular DNA and protein methyltransferases (PMTs) as well as demethylases involved in HIV infection. We describe the biology and function of DNA methyltransferases, and their controversial role in HIV infection. We further explain the biology of PMTs and their effects on lysine and arginine methylation of histone and nonhistone proteins. We end with a focus on protein demethylases, their unique modes of action and their emerging influence on HIV infection. An outlook on the use of methylation-modifying agents in investigational HIV cure strategies is provided.

A CRISPR/Cas9 screen identifies the histone demethylase MINA53 as a novel HIV-1 latency-promoting gene (LPG)

“…Dimethylated H3K36 (H3K36me2) on HIV-1 genes is induced upon TNFα activation in a P-TEFb-dependent manner (51). However, in a more recent study H3K36me2 seems not changed at the HIV-1 promoter upon TNFα activation (52). Trimethylated H3K36 (H3K36me3) was found across the transcribed region of HIV-1, mediated by Iws1, a protein binding to histone chaperone Spt6, which recruits the histone methyltransferase SETD2 to the RNAPII elongation complex (53).…”

X-Linked RNA-Binding Motif Protein Modulates HIV-1 Infection of CD4 + T Cells by Maintaining the Trimethylation of Histone H3 Lysine 9 at the Downstream Region of the 5′ Long Terminal Repeat of HIV Proviral DNA

“…For example, epigenetic modification of the 5=-LTR of HIV-1 proviral DNA tightly regulates viral gene transcription (5,6). This may be accomplished by recruitment of histone deacetylases, histone methyltransferases, or DNA methyltransferases; all of these enzymes can cause chromatin remodeling and nucleosome reorganization, leading to silencing of the viral promoter (6,7). The heterochromatin-associated histone marker H3K9me3 (trimethylation of histone H3 lysine 9) is known to suppress HIV-1 transcription, and thus, a reduction of H3K9me3 modification by treatment with chaetocin, a lysine-specific histone methyltransferase, reactivates HIV from latency (8)(9)(10).…”

Control of viral infections by epigenetic-targeted therapy

“…Moreover, sequential treatment with the DNMT inhibitor 5-aza-2′-deoxycytidine (5-AzadC) and HDAC inhibitors reactivates HIV-1 from latency [35]. In addition, it has been shown that the use of chaetocin and BIX-01294, specific inhibitors of HMT Suv39H1 and G9a respectively, resulted in HIV-1 recovery in resting CD4+ T cells in highly active antiretroviral therapy (HAART)-treated patients with undetectable viral load [36]. Another therapeutic approach could be considering tumor necrosis factor alpha (TNF)-based therapies, where combining HDAC inhibitors or HMT inhibitors with TNF, disrupts HIV-1 latency by triggering the activation of transcriptional activators like NF-κB and preventing the formation of heterochromatin, enhancing thus HIV-1 long terminal repeat (LTR) transcription and viral purge [37].…”