SMYD2-Mediated Histone Methylation Contributes to HIV-1 Latency

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 an 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. [Display omitted] •The histone lysine methyltransferase SMYD2 is an HIV-1 transcriptional repressor•SMYD2-mediated histone H4K20me1 methylation at the HIV LTR regulates latency•H4K20me1 reader protein L3MBTL1 associates with the HIV LTR in a SMYD2-dependent manner•SYMD2 knockdown or inhibition reactivates latent HIV-1 in cell lines and primary T cells Transcriptional latency of HIV is a last barrier to viral eradication. Boehm et al. identify the lysine methyltransferase SMYD2 as a regulator of HIV-1 latency via histone H4K20me1 methylation at the HIV LTR. Pharmacological SMYD2 inhibitors reactivate latent HIV-1 in primary T cells, suggesting a strategy for therapeutic latency reversal.