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Mapping of the hepatitis B virus attachment site by use of infection-inhibiting preS1 lipopeptides and tupaia hepatocytes
Authors:Glebe Dieter  Urban Stephan  Knoop Eva V  Cag Nilgün  Krass Peter  Grün Stefanie  Bulavaite Aiste  Sasnauskas Kestutis  Gerlich Wolfram H
Institution:Institute of Medical Virology, Justus-Liebig University Giessen, Germany. dieter.glebe@ciro.med.uni-giessen.de
Abstract:BACKGROUND & AIMS: Studies on the early steps in the life cycle of hepatitis B virus have been hampered by the lack of readily available target cells. In this study, we mapped a defined virus attachment site to primary hepatocytes that is essential for infection. METHODS: We used purified virus particles from human carrier plasma as an inoculum and primary cultures of tupaia hepatocytes as susceptible target cells and studied the inhibitory effect of amino-terminally acylated preS1-derived lipopeptides on infection interference. RESULTS: Infectivity of virus could be blocked efficiently in this system by amino-terminally acylated peptides containing amino acids 2-18 from the preS1 domain. The addition of amino acids 28-48 enhanced the inhibitory capacity, whereas amino acids 49-78 did not contribute to inhibition. Myristoylated preS1 peptides 2-48 bound strongly to tupaia hepatocytes but not to nonhepatic cells or rodent hepatocytes and thereby inhibited infection even at concentrations of 1 nmol/L completely. Particles consisting only of the small hepatitis B surface protein-the active component of current hepatitis B vaccines-did not bind at all to tupaia hepatocytes, but the addition of the preS1 domain to the particles allowed binding. CONCLUSIONS: The preS1 sequence 2-48 mediates attachment of the virus to its target cells, whereas the small surface protein seems to be involved in other steps. These findings indicate that the current subunit hepatitis B vaccines may be improved by the addition of distinct preS1 epitopes. Moreover, preS1 lipopeptides are promising candidates for specific antiviral therapy against hepatitis B infections.
Keywords:AA  amino acid  HBeAg  hepatitis B e antigen  HBs  hepatitis B surface  HBsAg  hepatitis B surface antigen  IC50  50% inhibitory concentration  LDH  lactate dehydrogenase  MAb  monoclonal antibody  MTT  3-(4  5-dimethylthiazol-2-yl)-2  5-diphenyltetrazolium bromide  SHBs  smallest of the 3 coterminal HBV surface proteins  THM  tupaia hepatocyte medium
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