1Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Im Neuenheimer Feld 345, Heidelberg, Germany; German Center for Infection Research, Heidelberg University. Electronic address: Stephan.Urban@med.uni-heidelberg.de.
2Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Im Neuenheimer Feld 345, Heidelberg, Germany; German Center for Infection Research, Heidelberg University.
3Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
4INSERM, U1052, Cancer Research Center of Lyon, Lyon University, Lyon, France.
Although there has been much research into the pathogenesis and treatment of hepatitis B virus (HBV) and hepatitis D virus (HDV) infections, we still do not completely understand how these pathogens enter hepatocytes. This is because in vitro infection studies have been performed in only primary human hepatocytes. Development of a polarizable, HBV-susceptible human hepatoma cell line and studies of primary hepatocytes from Tupaia belangeri have provided important insights into the viral and cellular factors involved in virus binding and infection. The large envelope glycoprotein (L) on the surface of HBV and HDV particles has many different functions and is required for virus entry. The L-protein mediates attachment of virions to heparan sulfate proteoglycans on the surface of hepatocytes. The L-protein's myristoylated N-terminal preS1 domain subsequently binds to the sodium-taurocholate co-transporting polypeptide (NTCP, encoded by SLC10A1) -the recently identified bona fide receptor for HBV and HDV. The receptor functions of NTCP and virus entry are blocked, in vitro and in vivo, by myrcludex B, a synthetic N-acylated preS1 lipopeptide. Currently, the only agents available to treat chronic HBV infection target the viral polymerase, and no selective therapies are available for HDV infection. It is therefore important to study the therapeutic potential of virus entry inhibitors, especially when combined with strategies to induce T-cell mediated killing of infected hepatocytes.