The type of chromatin structure around the LTR promoter of integrated HIV provirus provides critical signals that regulate transcription during both productive and latent HIV infections. The C-promoter binding factor-1 (CBF-1) is a potent and specific inhibitor of the HIV-1 transcription, which perform its function after binding to specific sites at HIV LTR. Here we demonstrate that the knockdown of endogenous CBF-1 in latently infected primary CD4+ T cells, using specific small hairpin RNAs (shRNA), resulted in the reactivation of latent HIV proviruses. By performing Chromatin immunoprecipitation (ChIP) assays, using latently infected primary T cells and Jurkat T-cell lines, we demonstrated that CBF-1 induces the establishment and maintenance of HIV latency by recruiting Polycomb Group (PcG/PRC) corepressor complexes or Polycomb repressive complexes 1 and 2 (PRC1 and PRC2). Knockdown of CBF-1 resulted in the dissociation of PRCs corepressor complexes and enhanced the recruitment of RNA polymerase II (RNAPII) at HIV LTR. Knockdown of certain components of PRC1 and PRC2 leads to the reactivation of latent proviruses. Similarly, treatment of latently infected primary CD4+ T cells with the EZH2 inhibitor, 3-deazaneplanocin A (DZNep), led to their reactivation.
Instead of inhibiting individual enzymes, targeting factors such as CBF-1, which mediate the establishment of multiple repressive epigenetic changes, could be more beneficial in designing strategies to reactivate and subsequently eliminate latent HIV reservoirs.
The George Washington University