cccDNA-bound histone acetylation status and the recruitment of chromatin-modifying enzymes onto the viral minichromosome change in relation to viral replication and IFN-α treatment. The drawings reflect what is observed in an in vitro replication system. The translation into the clinical scenario as it is observed in patients (lower boxes) is inferred, and it awaits to be confirmed by ex vivo experiments. In the context of high HBV replication and in the absence of IFN-α treatment, cccDNA-bound histones are hyperacetylated, cccDNA-associated chromatin is in an open configuration, pgRNA is actively transcribed, and HBV replication is unrestricted (left drawing). The clinical correlate is an active HBV carrier with high HBV viremia, reflecting high levels of intrahepatic viral replication and liver disease progression. In response to IFN-α, HDACs (HDAC1 and Sirt1) substitute HAT enzymes (p300, CBP, and P/CAF) on the cccDNA, and a PRC2-repressor complex is recruited. This leads to histone deacetylation/methylation at specific lysine residues, a “closed” chromatin configuration, and a striking reduction of pgRNA transcription, HBsAg synthesis, and HBV replication (middle drawing). In the clinical setting, this would translate into a rapid serum HBsAg decline and viral suppression (inactive carrier) with disease remission. When treatment is stopped, the chromatin changes imposed by IFN-α tend to persist (right drawing) resulting in the “off-therapy” maintenance of the virological suppression and clinical improvement (achieved in 30%–35% of HBeAg-positive patients and 20%–25% of HBeAg-negative patients). Darker forms in the middle and right drawings indicate components of the PRC2 complex whose recruitment has been directly investigated in this paper.