Cell type-specific mechanisms regulate hepatitis B virus transgene expression in liver and other organs

Intracellular expression of hepatitis B virus (HBV) was analysed in transgenic HBV mouse lines designated G7 and G26, the former lacking hepatitis B surface antigen (HBsAg) promoters. HBsAg mRNA expression was greater in the G26 line than in the G7 line, although in situ hybridization showed a qualitatively similar expression pattern in specific cell types. HBsAg mRNA was most abundant in hepatocytes, followed in magnitude by proximal renal tubular epithelial cells, pancreatic acinar cells, and epithelial cells of the gastric, small intestinal, and bronchiolar mucosae. In biliary epithelial cells, brain, spleen, large intestine, testis, heart, and skeletal muscle, HBsAg mRNA was undetectable. In cell transfection assays, the HBV enhancer/preS1 promoter efficiently expressed a luciferase reporter with appropriate upregulation by HNF-3 alpha and C/EBP alpha transcription factors in hepatocyte-derived cells but not in non-parenchymal epithelial liver cells or fibroblasts. These results suggest that cell-type specificity of HBV expression is regulated by interactions between viral elements and cellular transactivators. Variable expression of G7 and G26 HBV transgenes in epithelial cells combined with differences in transgene expression in similar sets of cells suggests at least two levels of regulation: one directing cell specificity of HBV expression and the other governing quantitative expression of HBV mRNA.