The immediate aim of this proposal is to apply the molecular biology of hepatitis delta virus (HDV) replication to the development of HDV as a vector for the delivery of specific biologically-active RNAs. The long term aim is to use such a modified HDV as an antiviral agent targeted against RNAs expressed as part of the replication cycle of an important human pathogen, hepatitis B virus (HBV). In this way it might be possible to provide significant clinical benefit to patients chronically infected with HBV, along with many other advantages, including minimal toxicity. Individuals chronically infected with HBV are at considerable risk of progressing to cirrhosis and liver cancer. Even partial suppression of HBV replication in these patients could rescue them from their life-threatening infection. Thus the proposal has two specific aims: i. Develop a series of modified HDV genomes that contain inserts capable of a biological activity against the RNAs of HBV and the related hepadnavirus, woodchuck hepatitis virus, WHV. These vectors will be tested in transfected cell lines for their anti-WHV and anti-HBV activities. Both theoretical and empirical approaches will be used to obtained an optimum anti-viral activity. ii. Test such a modified HDV genome in vivo, by first assembling it into virions and then using it to infect and act in woodchucks that have a chronic infection with woodchuck hepatitis virus (WHV). Woodchucks infected with WHV are known to be an excellent model for the human disease; the majority of the animals proceed to death by liver cancer. The proposed animal studies will first determine whether the assembled modified HDV genomes are infectious. Then an assessment will be made of WHV-specific anti-viral activity, leading to a search for an anti-disease activity. If the evaluation of the woodchuck results is agreed upon as promising, an effort will be made to instigate plans for a more detailed study of anti- disease activity in woodchucks and even for clinical studies with humans. However such plans are currently outside the scope of the proposal.
