Journal Article

Inhibition of the H3K27 demethylase UTX enhances the epigenetic silencing of HIV proviruses and induces HIV-1 DNA hypermethylation but fails to permanently block HIV reactivation

Dobrowolski, Curtis, Luttge, Benjamin, Cho, Won-Kyung, Nguyen, Kien, Karn, Jonathan, Shukla, Meenakshi

2021

Overview

One strategy for a functional cure of HIV-1 is “block and lock”, which seeks to permanently suppress the rebound of quiescent HIV-1 by epigenetic silencing. For the bivalent promoter in the HIV LTR, both histone 3 lysine 27 tri-methylation (H3K27me3) and DNA methylation are associated with viral suppression, while H3K4 tri-methylation (H3K4me3) is correlated with viral expression. However, H3K27me3 is readily reversed upon activation of T-cells through the T-cell receptor. In an attempt to suppress latent HIV-1 in a stable fashion, we knocked down the expression or inhibited the activity of UTX/KDM6A, the major H3K27 demethylase, and investigated its impact on latent HIV-1 reactivation in T cells. Inhibition of UTX dramatically enhanced H3K27me3 levels at the HIV LTR and was associated with increased DNA methylation. In latently infected cells from patients, GSK-J4, which is a potent dual inhibitor of the H3K27me3/me2-demethylases JMJD3/KDM6B and UTX/KDM6A, effectively suppressed the reactivation of latent HIV-1 and also induced DNA methylation at specific sites in the 5’LTR of latent HIV-1 by the enhanced recruitment of DNMT3A to HIV-1. Nonetheless, suppression of HIV-1 through epigenetic silencing required the continued treatment with GSK-J4 and was rapidly reversed after removal of the drug. DNA methylation was also rapidly lost after removal of drug, suggesting active and rapid DNA-demethylation of the HIV LTR. Thus, induction of epigenetic silencing by histone and DNA methylation appears to be insufficient to permanently silence HIV-1 proviral transcription.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Benzazepines - pharmacology / Biology and Life Sciences / Care and treatment / Cell activation / Cloning / Demethylation / Deoxyribonucleic acid / Development and progression / DNA / DNA methylation / DNA Methylation - drug effects / Epigenetic inheritance / Epigenetics / Gene expression / Gene silencing / Genetic aspects / Histone Demethylases - antagonists & inhibitors / Histones / HIV / HIV infection / HIV Infections - genetics / HIV Infections - metabolism / HIV Infections - virology / HIV-1 - drug effects / HIV-1 - physiology / Human immunodeficiency virus / Humans / Latent infection / Lymphocytes / Lymphocytes T / Lysine / Medicine and Health Sciences / Methylation / Methyltransferases / Population / Proviruses / Proviruses - drug effects / Pyrimidines - pharmacology / Structure / T cell receptors / T-cell receptor / Transcription / Virus Activation - drug effects / Virus Latency - drug effects / Virus research