DYSREGULATED SURFACE GENE-EXPRESSION FROM DISRUPTED HEPATITIS-B VIRUS GENOMES

During chronic infection by hepatitis B virus, the viral genome frequently integrates into the host chromosome, causing gross disruption and rearrangement of the viral DNA. We have obtained data showing that viral genomic disruptions which delete the enhancers from the transcribed region of the viral surface gene can lead to dysregulation of surface gene expression at the transcriptional level. Specifically, in cells transfected with such disrupted genomes, there is a decreased amount of transcripts coding for the major form of the surface protein but little change in the amount of transcripts coding for the large surface protein. In these cells, secretion of the surface proteins is blocked in the endoplasmic reticulum-Golgi intermediate compartment, consistent with previous work from other groups showing that relative overexpression of the large surface protein can block secretion of all forms of the surface protein. Our findings suggest that viral genomic rearrangements during integration may be a contributing factor in the pathogenesis of ground-glass hepatocytes, which contain large amounts of intracellular surface proteins as a result of a block in secretion and are frequently seen in the livers of patients with chronic hepatitis B.