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.

Keywords: HIV cure; demethylase inhibitors; histone demethylase; latency reactivation; methyltransferase; methyltransferase inhibitors.

FIG. 1.

Specificity of protein methyltransferases and demethylase LSD1 that target HIV-1-Tat at K51, R52, R53, and K71.

FIG. 2.

Histone lysine methyltransferases (KMT) and histone methyl marks implicated in HIV infection, showing residue-specific KMTs for H3K4/9/27/36 and H4K20. The majority of KMTs are highly specific for a single histone residue, whereas a few enzymes target multiple residues, as indicated.

FIG. 3.

Histone arginine methyltransferases (PRMT) and histone methyl marks implicated in HIV infection, showing residue-specific PRMTs for H3 and H4.

FIG. 4.

Histone demethylases and histone methyl marks implicated in HIV infection, showing residue-specific KMTs for H3K4, H3K9, and H3K27.