DELTA VIRUS--DELIVERY VECTOR/BIOLOGICALLY ACTIVE RNA'S

这项建议的直接目的是将分子生物学应用于 丁型肝炎病毒（HDV）复制到HDV的发展， 用于递送特定生物活性RNA的载体。 长 术语目的是使用这种修饰的HDV作为靶向的抗病毒剂 针对RNA表达的一个重要的复制周期的一部分， 人类病原体，B肝炎病毒（HBV）。 通过这种方式， 为慢性感染的患者提供显著的临床益处 与HBV，沿着许多其他优点，包括最小的毒性。 慢性HBV感染者有相当大的风险， 发展成肝硬化和肝癌 甚至部分抑制HBV 在这些患者中复制可以将他们从危及生命的疾病中拯救出来， 感染 因此，该提案有两个具体目标： I. 开发一系列修饰的HDV基因组， 抗HBV RNA和相关的 嗜肝DNA病毒，土拨鼠肝炎病毒，WHV。 这些载体将被测试 在转染细胞系中的抗WHV和抗HBV活性。 两 理论和经验的方法将被用来获得一个最佳的 抗病毒活性。 二. 在体内测试这种修饰的HDV基因组，首先将其组装成 病毒体，然后用它感染并作用于土拨鼠， 土拨鼠肝炎病毒（WHV）慢性感染。 土拨鼠 已知感染WHV的人是人类疾病的极好模型; 大多数动物因肝癌而死亡。 拟议 动物研究将首先确定组装的修饰HDV是否 基因组具有传染性。 然后，将对WHV特定的 抗病毒活性，导致对抗病活性的研究。 如果土拨鼠结果的评估被认为是有希望的， 将作出努力，鼓励制定计划，对反 土拨鼠的疾病活动，甚至用于人类的临床研究。 然而，这些计划目前不属于该提案的范围。

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.