Novel woodchuck hepatitis virus (WHV) transgene mouse models show sex-dependent WHV replicative activity and development of spontaneous immune responses to WHV proteins

The woodchuck model is an informative model for studies on hepadnaviral infection. In this study, woodchuck hepatitis virus (WHV) transgenic (Tg) mouse models based on C57BL/6 mice were established to study the pathogenesis associated with hepadnaviral infection. Two lineages ofWHVTg mice, harboring theWHVwild-type genome (lineage 1217) and a mutatedWHVgenome lacking surface antigen (lineage 1281), were generated.WHVreplication intermediates were detected by Southern blotting. DNA vaccines againstWHVproteins were applied by intramuscular injection. WHV-specific immune responses were analyzed by flow cytometry and enzyme-linked immunosorbent assays (ELISAs). The presence ofWHVtransgenes resulted in liver-specific but sex- and age-dependentWHVreplication in Tg mice. Pathological changes in the liver, including hepatocellular dysplasia, were observed in aged Tg mice, suggesting that the presence ofWHVtransgenes may lead to liver diseases. Interestingly, Tg mice of lineage 1281 spontaneously developed T- and B-cell responses toWHVcore protein (WHcAg). DNA vaccination induced specific immune responses toWHVproteins inWHVTg mice, indicating a tolerance break. The magnitude of the induced WHcAg-specific immune responses was dependent on the effectiveness of different DNA vaccines and was associated with a decrease inWHVloads in mice. In conclusion, sex- and age-dependent viral replication, development of autoimmune responses to viral antigens, pathological changes in the liver in WHV Tg mice, and the possibility of breaking immune tolerance toWHVtransgenes will allow future studies on pathogenesis related to hepadnaviral infection and therapeutic vaccines.