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HBV's unique mode of replication takes place in the nucleus of the infected host cell. Entrance into the cell takes place via receptor-mediated endocytosis as the envelope is shed and the viral core particle with the DNA viral genome is translocated into the nucleus of the host cell. The viral DNA is then repaired and transformed into closed cirucular DNA (cccDNA)by endogenous viral reverse transcriptase. Analogous to the DNA of retrovirus, HBV differs in that its cccDNA does not integrate and stays episomal.

RNA polymerase II then uses the cccDNA as a template to make greater-than-full length viral mRNA. Because the mRNA is longer than the cccDNA, repeated terminal ends are formed. Once formed, this "pregenome" (+) RNA exits the nucleus and is then translated to produce the core antigens and HBV polymerase it needs to encapsidate itself. The (-) DNA is then transcribed inside the capsid by reverse transcriptase. RNaseH then chews the (+)RNA away , leaving a small stretch of RNA, an undigested 5' oligoribonucleotide. This segment of RNA is comprised of a small sequence including the DR1 region. The oligomer is then annealed to the DR2 portion of the DNA at the 5' end. HBV polymerase then generates complementary (+)DNA using this oligomer as a primer. A portion of these newly synthesized plus strands of DNA are then packaged into virions with envelopes and the hepatitis B surface antigen (HBsAg) in the endoplasmic reticulum. The rest of the strands are sent back to the nucleus to serve as templates.