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

这项提议的直接目的是应用分子生物学 丁型肝炎病毒(HDV)复制对HDV作为一种 用于运送特定生物活性RNA的载体。《长河》 术语的目的是使用这种改良的HDV作为靶向的抗病毒药物 针对表达为复制周期一部分的RNA的重要 人类病原体，乙肝病毒(乙肝病毒)。这样一来，就有可能 为慢性感染患者提供显著的临床益处 与乙肝病毒，以及许多其他优势，包括最小的毒性。 慢性感染乙肝病毒的人有相当大的风险 进展为肝硬变和肝癌。甚至部分抑制乙肝病毒 这些患者的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，其中包含能够 抗乙肝病毒核糖核酸的生物活性及相关的 肝炎病毒，土拨鼠肝炎病毒，WHV。这些向量将被测试 对其进行抗WHV和抗乙肝病毒活性的研究。两者都有 将使用理论和经验方法来获得最优 抗病毒活性。 二、在体内测试这种修改后的HDV基因组，首先将其组装成 病毒粒子，然后用它感染土拨鼠，并在有 慢性感染土拨鼠肝炎病毒(WHV)。土拨鼠 感染WHV被认为是人类疾病的极好模型； 大多数动物都会因肝癌而死亡。建议数 动物研究将首先确定组装的改良型HDV 基因组是有传染性的。然后，将对特定于WHV的 抗病毒活性，导致人们寻找一种抗病活性。 如果对土拨鼠结果的评估被认为是有希望的，那么 将努力推动计划，以更详细地研究反 在土拨鼠中的疾病活动，甚至在人类的临床研究中。 然而，此类计划目前不在该提案的范围之内。

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.