Role of glycosaminoglycans for binding and infection of hepatitis B virus.
Many parts of the life cycle of hepatitis B virus (HBV) infection of hepatocytes have been unravelled, but the attachment and entry process leading to infection is largely unknown. Using primary Tupaia hepatocyte cultures as an in vitro infection system, we determined that HBV uses cell-surface heparan sulfate proteoglycans as low-affinity receptor, because HBV infection was inhibited by heparin (IC50: 5 microg ml(-1)) or other higher-sulfated polymers, but not by lower-sulfated glycosaminoglycans, such as chondroitin sulfate. Pretreatment of primary hepatocytes with heparinase decreased viral binding and inhibited HBV infection completely. Interestingly, after preS1-dependent viral binding at 16 degrees C to the cell surface, subsequent infection could still be inhibited by HBV preS1-lipopeptides, but not by heparin any more, suggesting a shift of the virus to a high-affinity receptor. In summary, we suggest following multistep attachment process: in vivo, HBV is initially trapped within the liver in the space of Dissé by heparan sulfate proteoglycans. Thereafter, HBV binds via its preS1 attachment site and the N-terminal myristic acid to a yet unknown, high-affinity receptor that confers uptake in a yet unknown compartment.
Leistner
Corinna M
CM
Institute of Medical Virology, Justus Liebig University, Frankfurter Str. 107, 35392 Giessen, Germany.
Gruen-Bernhard
Stefanie
S
Glebe
Dieter
D
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D019812:Heparan Sulfate Proteoglycans / Q000502:physiology*; D019763:Heparin Lyase / Q000378:metabolism; D006514:Hepatitis B Surface Antigens / Q000378:metabolism; D006515:Hepatitis B virus / Q000502:physiology*; D022781:Hepatocytes / Q000821:virology*; D006801:Humans; D011498:Protein Precursors / Q000378:metabolism; D011991:Receptors, Virus / Q000502:physiology*; D014417:Tupaia; D053585:Virus Attachment; D053586:Virus Internalization
D019812:Heparan Sulfate Proteoglycans; D006514:Hepatitis B Surface Antigens; D011498:Protein Precursors; D011991:Receptors, Virus; C050806:presurface protein 1, hepatitis B surface antigen; D019763:Heparin Lyase