Figure 2.

Annotated HBV genome and replication cycle. (A) The 4 overlapping ORFs and the 7 products encoded. Gene products are indicated by text boxes, with start and end positions derived using X02763.1 as a reference strain. The major functional domains of the P gene product are indicated (dotted lines). Large HBs consist of pre-S1, pre-S2, and S; medium HBs consist of pre-S2 and S; and small HBs consist of S only. The overlap of >1000 nucleotides between the P and S genes is the largest gene overlap of any known animal virus.³⁵ The near-complete negative DNA strand and partially complete positive DNA strands (dotted line indicates approximated missing region) also are shown, in addition to the position of EcoR1. The 5′ end of the complete negative-sense DNA strand is covalently bound to the viral RT. The complementary positive-sense DNA strand is partially complete, covering approximately two thirds of the viral genome.³⁶ The 5′ end of the incomplete strand is defined by a short oligo-ribonucleotide region; the 3′ end varies within and among hosts. (B) Replication cycle (adapted from Liang, special issue). (i) Infective HBV virions in serum, often referred to as Dane particles (diameter, 42 nm). The capsid structure has icosahedral symmetry: T = 4 (31 nm; 90% of population) and T = 3 (28 nm; 10% of population).37, 38 (ii) The virus enters hepatocytes by HSPG (low-affinity binding) and solute carrier family 10 member 1 (SLC10A1; also called sodium taurocholate co-transporting polypeptide NTCP; high-affinity binding). (iii) The molecular processes of un-coating and nuclear import are unclear but likely require cell proteins. (iv) Viral DNA enters the nucleus as RC-DNA. (v) Viral DNA is reconfigured as cccDNA within the nucleus by the cell’s DNA repair factors; this stable structure occurs in association with host histones that mediate DNA packaging. (vi) The open cccDNA structure is a template for host RNA polymerase II. (vii) DNA is transcribed to pre-genomic RNA intermediates in the nucleus, creating 4 mRNAs (blue): a 3.5-kb transcript encoding precore RNA (full-length pre-genomic RNA also shown in green); 2.4- and 2.1-kb mRNA transcripts for pre-S and S, respectively; and a 0.7-kb mRNA encoding the X protein. The RNA is transported to the cytoplasm, where it is translated to 7 viral proteins (short, medium, and long S proteins, core, e antigen, polymerase, and X protein). (viii) HBV RT produces a negative-strand DNA from pre-genomic RNA. The RNA template is degraded by RNase H, and then synthesis of the positive-strand DNA is initiated. HBV DNA is repackaged in relaxed form with other proteins inside the host cell. (ix) New virions and viral proteins are released into the blood. Excess HBsAg forms small noninfectious, subviral particles (∼20 nm diameter), and long filaments¹⁶¹; free HBeAg and capsids also are secreted. C, core; HBeAg, hepatitis B e antigen; HBx, hepatitis B X protein; HSPG, heparan sulfate proteoglycan; NCTP, Na⁺-taurocholate co-transporting polypeptide pol, polymerase; TP, terminal protein.