Life cycle of HBV. Attachment to liver-specific receptors (heparansulfate proteoglycan and NTCP, see text) leads to endocytosis of HBV and release of HBV core particles. These are transported to the nucleus and arrested at the nuclear pore complex where the HBV genome is released to the nucleus. In the nucleus, the viral DNA is “repaired” to the covalently closed circular (ccc) DNA and complexed with nucleosomes (not shown). In interaction with transcription factors (not shown), the ccc DNA is transcribed to the pregenomic and subgenomic mRNAs. The mRNAs are transported, mainly without splicing, to the cytoplasm. The two subgenomic mRNAs for the three HBs proteins are translated at the endoplasmic reticulum, assemble to subviral HBsAg particles and are secreted via the Golgi apparatus. In parallel, the pregenomic mRNA is translated in the cytosol to the HBV core protein and the viral polymerase, whereby the three components assemble to the immature core particle. The HBV genomes mature within the core particles via reverse transcription of the pregenomic mRNA to DNA. The mature core particles can migrate again to the nuclear pore complex or are enveloped by the surface proteins and secreted via the multivesicular bodies (MVB).