FIG. 6.

Model of HBV infection and its relationship to methylation. In this model, HBV replication is recognized by the infected cell, triggering activation of DNMTs. Once activated, DNMTs can methylate CpG dinucleotides in viral DNA, turning off viral RNA production. The presumed target is cccDNA. However, the increased expression of DNMTs is not exclusively to the benefit of the cell. DNMTs can also be co-opted/dysregulated by the viral X protein, diverting the DNMTs to methylate and downregulate genes that are disadvantageous to viral replication. Also, over time host tumor suppressor promoters can be methylated, leading to hepatocellular carcinomas with a methylator phenotype.