This is in contrast to studies in which naked HBV DNA, covalently-closed circular DNA, and pre-genomic RNA were sensed in PHHs and human hepatoma cells by sufficient levels of cytoplasmic cGAS, nuclear IFI16, or nuclear and cytoplasmic RIG-I, respectively, leading to a pathway activation of the respective receptors (47–49). Here, IFI16 is linked to hepatocellular carcinoma.