New insights into hepatitis B and hepatitis delta virus entry

Notwithstanding the medical importance of the HBV infection, our understanding of how this pathogen enters hepatocytes is incomplete. This reflects a long-lasting dependence of in vitro infection studies solely on primary human hepatocytes, which are difficult to obtain and maintain in a susceptible state. The establishment of a polarizable HBV-susceptible human hepatoma cell line (HepaRG) and the utilization of Tupaia belonged hepatocytes (PTHs) resolved this issue. Since then, important insight into viral and cellular determinants participating in HBV binding and infection have been achieved. We now know that the large viral surface protein (L) plays a pivotal role in HBV entry. It mediates diverse functions, commencing binding of virions to heparan sulfate proteoglycans at the hepatocytes surface as a prerequisite for entry. Subsequently, (a) highly specific event(s) involving the myristoylated N-terminal preS1 subdomain of L, as well as the cytosolic and antigenic loops of the S-domain, initiates a series of less well understood steps, resulting in a pH independent, reduction-sensitive fusion of the viral membrane with a cellular membrane. One of these steps is highly sensitive to synthetic N-acylated preS1 lipopeptides and can be blocked in vitro and in vivo at picomolar concentrations. This opens novel therapeutic options addressing virus entry. Future approaches aiming at the elucidation of HBV hepatotropism, the identification of (a) specific receptor(s), the clarification of the endocytic entry pathway and imaging of fluorescently-labeled virions will allow us to decipher more precisely the HBV entry pathway in the near future. Furthermore, clinical efficacy studies with HBV-preS-derived lipopeptides will tell us whether entry inhibition is a passable way to defend acute and chronic HBV and hepatitis delta virus infections.