Identification of new targets for alphavirus inhibition

描述(由申请人提供)：Togaviridae家族的阿尔法病毒属成员在世界范围内引起重大疾病，并可能被用作生物恐怖主义武器。目前还没有针对感染这些病毒的特效药，这些病毒会导致发烧、皮疹、关节炎、脑炎和死亡。这项建议的目的是确定宿主抗病毒因子，并确定宿主与病毒因子之间的相互作用，这些因素对病毒复制至关重要。以Sindbis病毒为模型系统，将采取两种方法。首先，将筛选在敏感细胞系中表达的宿主基因库，以确定能够抑制Sindbis介导的细胞死亡的宿主因子。识别出的基因或部分基因可以直接作为抗病毒药物发挥作用，或者以显性负向方式抑制基本的病毒-宿主相互作用。第二种方法需要筛选一个表达辛德比斯病毒基因组随机片段的文库，以寻找那些可以作为基本病毒-宿主或病毒-病毒相互作用的显性负抑制因子的片段。这样确定的宿主基因和病毒片段将为深入了解甲型病毒与宿主的相互作用提供依据。未来的研究旨在了解受影响的病毒的范围和抑制发生的分子机制，可能会导致合理设计用于医疗和生物防御的抗病毒治疗的潜在靶点。

DESCRIPTION (provided by applicant): Members of the alpha virus genus of the Togaviridae family cause significant disease worldwide and are of concern for possible use as bioterrorism weapons. There is no specific therapy for infection with these viruses, which can result in fever, rash, arthritis, encephalitis and death. The objectives of this proposal are to identify host antiviral factors and to identify interactions between host and viral factors that are essential for viral replication. Using Sindbis virus as a model system, 2 approaches will be undertaken. First, libraries of host genes expressed in susceptible cell lines will be screened to identify host factors that can inhibit Sindbis-mediated cell death. The identified genes, or portions of genes, may be functioning directly as an antiviral agent, or in a dominant negative manner to inhibit an essential virus-host interaction. The second approach entails screening a library expressing random fragments of the Sindbis virus genome for those fragments that can act as dominant negative inhibitors of essential virus-host, or virus-virus, interactions. The host genes and viral fragments so identified will provide insight into alphavirus-host interactions. Future studies aimed at understanding the range of viruses affected and the molecular mechanism through which the inhibition occurs might lead to potential targets for the rational design of antiviral therapies for medical and biodefense use.