Direct Acting Antivirals for the Treatment of Chronic Viral Hepatitis

Figure 2

The replication strategy of hepatitis B virus and stages of: (A) binding of the viral polymerase to ε and synthesis of a short primer using as template the nucleotide sequence of the bulge as shown. (B) Translocation of the polymerase/primer complex to the 3′ end of the pgRNA and base-pairing with DR1. (C) (−)-DNA strand synthesis and degradation of the pgRNA template by the RNase H domain of the polymerase, apart from its terminal 18 or so bases. These bases constitute the RNA primer which initiates (+)-DNA strand synthesis (D). Translocation of the primer to the 5′ end of the newly synthesised (−)-DNA strand and annealing with the homologous DR2 region leads to (+)-DNA strand synthesis. This proceeds in the direction shown by the arrow, which necessitates yet another translocation event to the 3′ end of the (−)-DNA strand. Both of these events are most likely facilitated by the effective circularisation of the (−)-DNA strand. This becomes possible, as a result of the covalent attachment of the 5′ end of the strand to the polymerase, which is maintained during continued synthesis of the (−)-DNA strand. Thus, the two ends of the strand are brought into close proximity with each other (E). Points of action of nucleos(t)ide analogues are shown by open arrows.