Axl signaling abrogated HBV clearance in a HBV persistence mouse model (P1360)

Abstract

Abstract Persistent HBV infection is a major etiology for chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Whilst most HBV infection in the adult resolves after the acute phase, over ninety percent of HBV infection in neonates and children leads to chronic HBV persistence. By using hydrodynamic injection of the replication-competent HBV plasmid, pAAV-HBV, we established a mouse model of HBV persistence in which a state of HBV persistence can be generated in 4-6 w/o C57BL/6 young mice, but not in adult mice of older than 10 w/o. We found that there is higher hepatic interferon (IFN)-a/b expression in the young mice after pAAV-HBV injection compared to the adult mice. In addition, we found that excessive IFN-a/b expression of the young mice was associated with the induction of the Axl negative regulatory pathway. We hypothesize that IFN-a/b-induced Tyr3-Axl-MerTk (TAM) feedback regulation hampered the generation of effective anti-HBV immunity, which in turn facilitated the establishment of HBV persistence in the young mice. In accordance with this hypothesis, we found that HBV persistence in the adult mice can be increased by augmented Axl expression. IFN-a/b are well-known for their antiviral effects; however, accumulating studies also demonstrated an immune regulatory function. In line with the previous studies, our findings suggest that Axl signaling suppresses the mounting of anti-HBV immunity, possibly due to the feedback regulatory pathway of IFN-a/b.