Fig. 6

Molecular mechanism of HIV-1 proviral latency and strategies to disrupt latency by epi-inhibitors. The HIV-1 LTR is flanked by nuc-0 to nuc-1. During HIV-1 latency, nuc-1 is epigenetically silenced by several mechanisms. PRC2 recruits at nuc-1 and deposit the trimethylation marks onto H3K27. The repressive mark is recognized by CBX protein of PRC1. RING1, a component of PRC1, adds ubiquitination marks at H2K119. Nuc-1 is also epigenetically silenced by several transcription factors such as YY-1, CTIP-2, NF-kB p50/p50, homodimers. The corepressor CTIP-2 binds to Sp1 transcription factor at three sites in viral promoter and recruits HDACs and HMTs. Suv39h1 trimethylates H3K9 resulting in the recruitment of HP1. The HMT G9a mediates dimethylation of H3K9, which is also implicated in HIV-1 latency. The viral promoter is hypermethylated by DNMT at two CpG islands. PRC2 also recruits DNMTs promoting more silenced chromatin state. Various compounds have been proposed to reactivate the HIV-1 from latency including HMTIs (pyridone 6, chaetocin, UNCO638, UNC0642) to target HMTs (PcG of proteins, Suv39H1, G9a), HDACIs (panobinostat, romidepsin, valproic acid, vorinostat) to target hypoacetylated viral promoter, and DNMTIs (decitabine, 5-azacitidine) to target DNA methylation and Akt agonist to downregulate the PRC2