Fig. 2

Epigenetic control of HIV-1 transcription initiation. The structure of the HIV-1 LTR and flanking nucleosomes (Nuc-0, Nuc-1, and Nuc-2) is shown at the center. In the latent state, the proviral promoter is bound by repressive trans-acting factors, including CBF-1, YY1, and NF-κB p50/p50, which direct the recruitment of histone deacetylase enzymes (HDACs). Subsequent occupancy of the promoter by the polycomb repressive complex 2 (PRC2) and EHMT2 results in the methylation of the deacetylated histone H3 at Lys27 and Lys9 positions, respectively. PRC2 also functions to recruit the polycomb repressive complex 1 (PRC1), in part via the binding of CBX4 to H3K27me3. Methylation of the 5’ CpG island (5ʹ CpGI) by DNMT1 and DNMT3a promotes the repressive histone methylation status of Nuc-1 by mediating the recruitment of UHRF1 and the HDAC-containing NuRD complex through MBD2. The SWI/SNF chromatin remodeling complex BAF interacts with Nuc-1 and is required to maintain increased Nuc-1 density around the HIV-1 transcription start site. By associating with CBX4, CAF-1, and PML, latent proviruses are likely to be situated in liquid–liquid phase-separated (LLPS) nuclear condensates that may concentrate transcriptionally poised genes with repressive heterochromatic features. CAF-1 may also play a central role in the initial assembly of nucleosomes at the provirus following integration and DNA replication. Typical of bivalent promoters, the HIV-1 LTR is in a reversible epigenetically repressed state poised for rapid inducible transcription. Recruitment of histone acetyltransferases, the H3K27me3 demethylase UTX/KMDA, and the PBAF SWI/SNF remodeling complex to the HIV-1 promoter following the nuclear induction of transcription activators enables the displacement of Nuc-1 and Nuc-2 thereby stimulating viral transcription initiation