Src kinases involved in hepatitis B virus replication

Chronic infection by hepatitis B virus is a leading cause of human liver ca ncer and liver disease. The hepatitis B virus HBx protein is a regulatory f actor that is essential for virus infection in mammals and is implicated in development of liver cancer and liver disease. Among the reported activiti es of HBx is the ability to stimulate Src tyrosine kinases, Ras-GTPases and transcriptional activation. We now demonstrate that HBx activation of Src tyrosine kinases, but not Ras, promotes a high level of viral replication i n cell culture. HBx is shown to stimulate reverse transcription of the vira l pregenomic mRNA into genomic DNA through a Src-mediated pathway in tissue culture cells. Targeted inhibition of Src tyrosine kinase activity, mutati onal inactivation of the HBx gene or retargeting of HBx to the nucleus to a bolish cytoplasmic signal transduction activity, are shown to impair viral reverse transcription strongly. These studies implicate HBx stimulation of the Src family of tyrosine kinases in stimulation of viral polymerase activ ity.