A Slow Maturation Process Renders Hepatitis B Virus Infectious.
Hepatitis B virus (HBV) replication is strictly limited to the liver. Virions attach to hepatocytes through interactions of the viral PreS envelope protein domain with heparan sulfate proteoglycans (HSPGs). However, HSPG is ubiquitously present on many cell types, suggesting that HBV employs mechanisms to avoid attachment at extrahepatic sites. We demonstrate that HBV particles are released from cells in an inactive form with PreS hidden in the interior. These HSPG-non-binding (N-type) particles develop receptor binding competence by translocating PreS across the envelope onto their surface. Conversion into HSPG-binding (B-type) particles occurs spontaneously and renders HBV infectious. Low-dose inoculation of mice with human liver xenografts demonstrates superiority of N-type particles in establishing infections, while mature B-type virions, generated via N-type conversion, are profoundly impaired, correlating with non-selective accumulation in extrahepatic tissues. This dynamic topology switch represents a maturation process utilized by HBV to most likely avoid non-productive docking outside the liver.
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany. Electronic address: stefan.seitz@med.uni-heidelberg.de.
Stefan
S
Seitz
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
Caroline
C
Iancu
Department of Medicine and Center for Internal Medicine, University Medical Center, Hamburg-Eppendorf, 20246 Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner Sites, 20246 Hamburg and 69120 Heidelberg, Germany.
Tassilo
T
Volz
Department of Nuclear Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
Walter
W
Mier
Department of Medicine and Center for Internal Medicine, University Medical Center, Hamburg-Eppendorf, 20246 Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner Sites, 20246 Hamburg and 69120 Heidelberg, Germany.
Maura
M
Dandri
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner Sites, 20246 Hamburg and 69120 Heidelberg, Germany.
Stephan
S
Urban
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner Sites, 20246 Hamburg and 69120 Heidelberg, Germany; Division of Virus-Associated Carcinogenesis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. Electronic address: ralf.bartenschlager@med.uni-heidelberg.de.
Ralf
R
Bartenschlager
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006514:Hepatitis B Surface Antigens / Q000378:metabolism*; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D016031:Liver Transplantation; D051379:Mice; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D053585:Virus Attachment
D006514:Hepatitis B Surface Antigens