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Journal of Virology, March 2006, p. 2797-2807, Vol. 80, No. 6
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.6.2797-2807.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Immune Suppression Uncovers Endogenous Cytopathic Effects of the Hepatitis B Virus

Center for Vaccinology, Ghent University and Hospital, Building A, First Floor, De Pintelaan 185, B-9000 Ghent, Belgium,¹ Department of Morphology and Molecular Pathology, U.Z.-K.U. Leuven, Minderbroederstraat 12, B-3000 Leuven, Belgium,² Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037,³ Department of Surgery, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, London, United Kingdom,⁴ Molecular Hepatology Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa⁵

Received 3 August 2005/ Accepted 27 December 2005

It is generally accepted that the host's immune response rather than the virus itself is causing the hepatocellular damage seen in acute and chronic hepatitis B virus (HBV) infections. However, in situations of severe immune suppression, chronic HBV patients may develop a considerable degree of liver disease. To examine whether HBV has direct cytopathic effects in severely immune compromised hosts, we have infected severe combined immune deficient mice (uPA-SCID), harboring human liver cells, with HBV. Serologic analysis of the plasma of HBV-infected animals revealed the presence of extremely high amounts of viral genomes and proteins. Histological analysis of the livers of uPA-SCID chimeras infected with HBV for more than 2 months showed that the majority of human hepatocytes had a ground-glass appearance, stained intensely for viral proteins, and showed signs of considerable damage and cell death. This histopathologic pattern closely resembles the picture observed in the livers of immunosuppressed HBV patients. These lesions were not observed in animals infected with HBV for less than 1 month. Ultrastructural analysis of long-term-infected hepatocytes showed a highly increased presence of cylindrical HBsAg structures, core particles, and Dane particles compared to short-term-infected hepatocytes. These long-term-infected hepatocytes also contained elevated amounts of HBV cccDNA. In conclusion, HBV causes dramatic intracellular changes and hepatocellular damage in the human hepatocytes that reside in a severely immune deficient mouse. These lesions show much resemblance to the ones encountered in immunosuppressed chronic HBV patients. Our observations indicate that HBV may be directly cytopathic in conditions of severe immune suppression.

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