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Journal of Virology, August 2003, p. 8882-8892, Vol. 77, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.16.8882-8892.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Endocytosis of Hepatitis B Immune Globulin into Hepatocytes Inhibits the Secretion of Hepatitis B Virus Surface Antigen and Virions

Ralf Schilling,1 Samreen Ijaz,2 Michail Davidoff,3 Jia Yee Lee,4 Stephen Locarnini,4 Roger Williams,1 and Nikolai V. Naoumov1*

Institute of Hepatology, Department of Medicine,1 Windeyer Institute, Department of Virology, University College London, London WC1E 6HX, United Kingdom,2 Institute for Microscopic Anatomy, University Hospital Eppendorf, D-20246 Hamburg, Germany,3 Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria 3051, Australia4

Received 16 April 2003/ Accepted 5 May 2003

Hepatitis B immunoglobulin is used for prophylaxis against hepatitis B virus (HBV) and is thought to act by neutralization of virions and hepatitis B virus surface antigen (HBsAg)-containing particles in circulation. Using a panel of hepatocyte-derived cell lines, the present study investigated in vitro whether HBs-specific immunoglobulin G (IgG) is internalized in hepatocytes and whether it interacts with HBsAg in the cells. By immunoelectron microscopy and immunoblotting, human IgG and FcRn receptor for IgG were demonstrated on cellular membranes and in cytoplasmic extracts, irrespective of the HBsAg status of the cells. Furthermore, HBsAg and anti-HBs were shown to be colocalized in the same cellular compartment by two-color confocal microscopy. Endocytosis of HBs-specific IgG caused intracellular accumulation of HBsAg in a dose-dependent manner and inhibited the secretion of HBsAg and HBV virions from the cells. These effects were not observed with F(ab)2 fragments or nonimmune IgG as controls. The specificity of intracellular HBsAg- anti-HBs interaction was further investigated in cells transfected with HBV genomes expressing wild-type HBsAg or immune escape HBsAg (with a G145R mutation). Monoclonal anti-HBs markedly reduced the secretion of wild-type HBsAg, while the secretion of mutant HBsAg was not affected. These results suggest that HBs-specific IgG binds to hepatocytes and interacts with HBsAg within the cells. This may be relevant for the selection of surface antibody escape mutations.

* Corresponding author. Mailing address: Institute of Hepatology, University College London, 69-75 Chenies Mews, London WC1E 6HX, United Kingdom. Phone: 44-20-7679 6512. Fax: 44-20-7380 0405. E-mail: n.naoumov{at}ucl.ac.uk.

Journal of Virology, August 2003, p. 8882-8892, Vol. 77, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.16.8882-8892.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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