Mechanism of inhibition of +RNA virus replication by cyclophilins

描述（由申请人提供）：宿主因子是RNA病毒病理、宿主-病毒相互作用和病毒进化的关键决定因素。最近对几种病毒的全基因组筛选发现了几种直接抑制+RNA病毒积累的宿主蛋白。这些宿主蛋白可能是宿主抗病毒先天系统的新成分。在已鉴定的抑制性宿主蛋白中有亲环蛋白家族，它对几种病毒有效。亲环蛋白是一个广泛存在的高度保守的蛋白家族，具有肽基脯氨酸异构酶和蛋白伴侣活性。亲环蛋白与多种疾病有关，如人类癌症、神经退行性疾病和病毒感染。确定宿主因子（如亲环蛋白）的抑制机制是当前病毒学研究的一个重要前沿。与传统抗病毒药物相比，已确定的抑制性宿主因子可用于抗病毒方法，包括对许多相关病毒的更广泛的抗病毒作用和更持久的抗病毒作用，因为病毒可能有更困难的挑战来进化逃避这些宿主因子的突变体。由于宿主细胞的功能冗余或缺乏对其功能的了解，我们对宿主因子抑制活性机制的理解进展缓慢。然而，易于处理的病毒-宿主系统，如番茄丛矮病毒（TBSV）和酵母作为模型宿主，可以极大地有助于我们了解这些宿主蛋白的功能。这个项目可能会促进我们对亲环蛋白在病毒-宿主相互作用中的作用的理解。这一进展可以极大地帮助其他科学家研究不易处理但具有破坏性的病毒病原体，目前类似的研究还不可行。获得的知识不仅对TBSV有用，而且对其他重要的人类病原体也有用，如西尼罗河病毒、登革热病毒和其他黄病毒和鼠疫病毒，因为它们的复制酶蛋白相似。总的来说，TBSV的主要进展将刺激研究RNA复制和重要人类病原体宿主-病原体相互作用的新方法的发展。以下是该建议的主要优势：(i)病毒RNA复制显然对病毒感染生物体具有极其重要的意义。（二）亲环蛋白是影响病毒和其他人类疾病的主要蛋白质，但其功能作用目前尚未明确。（iii）研究者开发的酵母和真实无细胞检测相结合的方法是目前研究宿主因子参与病毒RNA复制和病毒发病机制最有效的方法。（四）这项研究有望在病毒复制、宿主-病毒相互作用和病毒适应宿主等领域取得突破性成果，从而造福社会。

DESCRIPTION (provided by applicant): Host factors are key determinants of RNA virus pathology, host - virus interactions, and evolution of viruses. Recent genome-wide screens with several viruses have identified several host proteins, which directly inhibit +RNA virus accumulation. These host proteins might be novel components of the host innate systems against viruses. Among the identified inhibitory host proteins are the family of cyclophilins, which are effective against several viruses. Cyclophilins are a large family of ubiquitous, highly conserved proteins that have peptidyl-prolyl isomerase and protein chaperone activities. Cyclophilins are involved in several diseases, such as human cancers, neurodegenerative diseases and viral infections. Determining the mechanism of inhibition by host factors, like cyclophilins, is a major frontier in current virology research. The identified inhibitory host factors could be used in antiviral approaches with several advantages over traditional antivirals, including broader antiviral effects against many related viruses and more durable antiviral effects since viruses may have a more difficult challenge to evolve mutants that evade these host factors. Progress in our understanding of the mechanisms of the inhibitory activity of host factors is slow due to functional redundancy in the host cells or lack of knowledge about their functions. However, easily tractable virus - host systems, such as Tomato bushy stunt virus (TBSV) and yeast as a model host can greatly contribute to our understanding of the functions of these host proteins. This project will likely advance our understanding of the role of cyclophilins in virus-host interactions. This advance could immensely help other scientists working with less tractable, but devastating viral pathogens for which similar studies are currently not yet feasible. The gained knowledge will not only be useful for TBSV, but to other significant human pathogens, such as West Nile virus, Dengue virus and other flaviviruses and pestiviruses, due to the similarity of their replicase proteins. Collectively, the major advances with TBSV will stimulate development of new approaches for studying RNA replication and host - pathogen interactions for important human pathogens. The following are the major strengths of the proposal: (i) Viral RNA replication is clearly of immense importance for viruses to infect living organisms. (ii) Cyclophilins are major proteins affecting viral and other human diseases, yet their functional roles are currently poorly defined. (iii) The combination of yeast and authentic cell-free assay developed by the investigator is currently the most potent for studying the mechanism of host factors involvement in viral RNA replication and viral pathogenesis. (iv) The research holds promise of benefiting society by leading to groundbreaking results in the area of virus replication, host-virus interactions and the adaptation of viruses to their hosts.