SMYD2-Mediated Histone Methylation Contributes to HIV-1 Latency

Abstract

Summary Transcriptional latency of HIV is a last barrier to viral eradication. Chromatin-remodeling complexes and post-translational histone modifications likely play key roles in HIV-1 reactivation but the underlying mechanisms are incompletely understood. We performed a RNAi-based screen of human lysine methyltransferases and identified the SET and MYND domain-containing protein 2 (SMYD2) as an enzyme that regulates HIV-1 latency. Knockdown of SMYD2 or its pharmacological inhibition reactivated latent HIV-1 in T-cell lines and in primary CD4+ T cells. SMYD2 associated with latent HIV-1 promoter chromatin, which was enriched in monomethylated lysine 20 at histone H4 (H4K20me1), a mark lost in cells lacking SMYD2. Further, we find that lethal 3 malignant brain tumor 1 (L3MBTL1), a reader protein with chromatin-compacting properties that recognizes H4K20me1, was recruited to the latent HIV-1 promoter in a SMYD2-dependent manner. We propose that a SMYD2-H4K20me1-L3MBTL1 axis contributes to HIV-1 latency and can be targeted with small-molecule SMYD2 inhibitors.

NF-κB-Chromatin Interactions Drive Diverse Phenotypes by Modulating Transcriptional Noise

“…Other epigenetic modifications have also been implicated in HIV latency (Blazkova et al, 2009; Boehm et al, 2017; Pearson et al, 2008); it is likely that some of these also regulate viral phenotypic diversity. One possibility is that different chromatin modifications determine different timescales of provirus epigenetic memory (Bintu et al, 2016).…”

HIV Latency Gets a New Histone Mark

“…“Reader” can specifically recognize chromatin modifications, whereas “eraser” can remove modifications. The Boehm et al (2017) study indicates that SMYD2, and likely L3MBTL1, are novel regulators and pharmacological targets of HIV-1 latency. Epigenetic events under the control of host cell coregulators of HIV transcription and latency are of particular interest for “shock and kill” approaches of HIV-1 eradication for a functional cure.…”

“…In this issue of Cell Host & Microbe, Boehm et al (2017) report on an RNAi screen to query KMTs involved in HIV latency reversal and identify SMYD2, a member of a family of non-canonical SET-domain-containing chromatin modifiers, as an HIV provirus corepressor. Knockdown of SMYD2 relieves HIV latency in model reporter cell lines, and the bioavailable SMYD2 inhibitor AZ391 increases cellular transcript levels of HIV in CD4+ T cells from patients with suppressed viral load.…”

“…The H4K20me1 mark is known to recruit a chromatin reader protein named L3MBTL1, which plays a role in heterochromatin formation. SMYD2 knockdown or TNFa treatment precluded L3MBTL1 occupancy at the HIV promoter, suggesting that monomethylation of H4K20 by SMYD2 is a critical mechanism of proviral transcriptional latency (Boehm et al, 2017). Therefore, inhibitors of SMYD2 such as AZ391 may represent a new class of latency-reversing agents (LRAs).…”

HIV Latency Reversal Agents: Effective for Cure?

“…Clinical trials with these agents, albeit have shown modest to no viral rebound. Other epigenetic modifiers like bromodomain inhibitors [17,18] and SMYD inhibitors (methylation blockers) [19] have also been the target for HIV reactivation with limited success so far.…”