Strategies to inhibit entry of HBV and HDV into hepatocytes.
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 only been performed in 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 (L) protein 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 myristoylated N-terminal preS1 domain of the L protein subsequently binds to the sodium taurocholate cotransporting 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 immune-mediated killing of infected hepatocytes.
Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany; German Center for Infection Research, Heidelberg University, Heidelberg, Germany. Electronic address: stephan.urban@med.uni-heidelberg.de.
Stephan
S
Urban
Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany; German Center for Infection Research, Heidelberg University, Heidelberg, Germany.
Ralf
R
Bartenschlager
Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
Ralf
R
Kubitz
INSERM Unité 1052, Cancer Research Center of Lyon, Lyon University, Lyon, France.
Fabien
F
Zoulim
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D019812:Heparan Sulfate Proteoglycans / Q000502:physiology; D006509:Hepatitis B / Q000188:drug therapy / Q000503:physiopathology; D006515:Hepatitis B virus / Q000472:pathogenicity / Q000502:physiology*; D003699:Hepatitis D / Q000188:drug therapy / Q000503:physiopathology; D003698:Hepatitis Delta Virus / Q000472:pathogenicity / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology / Q000821:virology*; D006801:Humans; D014759:Viral Envelope Proteins / Q000502:physiology; D053586:Virus Internalization / Q000187:drug effects*
D000998:Antiviral Agents; D019812:Heparan Sulfate Proteoglycans; D014759:Viral Envelope Proteins
Hepatitis B Virus Receptor; SCL10A1; Sodium Taurocholate Cotransporting Polypeptide