Figure 1.

HBV replication. 1. Virus binding and entry into the host cell (large rectangle). 2. Intracellular trafficking and delivery of rcDNA to the nucleus (large circle). 3. Conversion of rcDNA to cccDNA, or integration of the double-stranded linear (DSL) DNA into cell DNA (3a). 4. and 4a. Transcription to synthesize viral RNAs (wavy lines), including the core (C) mRNA for both the core and the reverse transcriptase (RT) proteins; large surface (LS) mRNA for the large (L) surface or envelope protein; small (S) mRNA for the middle (M) and small (S) envelope proteins; X mRNA for the X protein; and PreC mRNA for the PreCore protein. The C mRNA is also the pgRNA: the template for producing progeny viral DNA via reverse transcription. 5. Translation to synthesize viral proteins. 6. Assembly of the pgRNA- (and RT-) containing NC, or alternatively, empty capsids (6a). 7. Reverse transcription of pgRNA to synthesize the (–) strand single-stranded (SS) DNA and then rcDNA. 8. Nuclear recycling of progeny rcDNA to form more cccDNA (intracellular cccDNA amplification). 9. Envelopment of the rcDNA-containing NC and secretion of complete virions, or alternatively, secretion of empty virions (9b) or HBsAg spheres and filaments (9a). Processing of the PreCore protein and secretion of HBeAg are shown in 9c. The secretion of putative RNA virions is not yet resolved (9?). The different viral particles outside the cell are shown with their approximate concentrations in the blood of infected persons indicated: the complete, empty, or RNA virions as large circles (outer envelope) with an inner diamond shell (capsid), with or without rcDNA (gapped, double concentric circle) or RNA (wavy line) inside the capsid, respectively; HBsAg spheres and filament as small circles and cylinders. Approximate concentrations of the different viral particles in the blood of infected patients are indicated but can vary among patients and over time in the same patient. Intracellular capsids, diamonds, with either viral pgRNA, SS ([–] strand) DNA (straight line), rcDNA, or empty. Dashed lines of the diamond in the rcDNA-containing mature NC and the complete virion, destabilization of the mature NC. Boxed letters, viral proteins translated from the mRNAs. Filled small circle inside the capsids, the RT protein binding to the 5′ end of the pgRNA and covalently attached to the 5′ end of the (–) strand DNA. Twisted circle, cccDNA. The thin dashed line and arrow indicate that HBeAg (small orange circles outside the cell) is frequently decreased or lost late in infection. For simplicity, synthesis of the minor DSL form of the genomic DNA in the mature NC, its secretion in virions, and infection of DSL DNA-containing virions are not depicted here, as are the functions of X. Adapted from Hu and Liu,¹⁷⁷ with the Creative Commons Public License, https://creativecommons.org/licenses/by/4.0/legalcode.