Structural studies of viral replication and invasion

摘要 病毒是人类健康的主要威胁。我们的实验室使用各种结构生物学技术， 剖析病毒如何复制和入侵宿主细胞或其基因组的分子机制。我们的一个领域 主要的兴趣是逆转录病毒的整合，这是逆转录病毒生命周期中的关键步骤， 将逆转录的病毒基因组插入宿主染色体。我们将在最近的结构上 人T细胞白血病病毒和劳斯肉瘤病毒的研究，并进一步研究 宿主因子在这些逆转录病毒整合过程中的作用。我们正在努力的另一个领域是 冠状病毒RNA基因组的复制和宿主细胞入侵。特别是，我们感兴趣的是， 编码的核糖核酸外切酶复合物促进冠状病毒的大RNA基因组的忠实复制， 以及这种独特的校对活动如何被小分子调节。我们也在调查 通过新型抗体和抗体模拟物抑制冠状病毒刺突蛋白的受体结合。 总的来说，本申请中提出的研究将有助于更好地了解重要的基于RNA的人类基因组。 病原体，并可以帮助开发抗病毒策略，或者，基因传递工具， 研究或基因治疗应用。

Abstract Viruses are a major threat to human health. Our laboratory uses various structural biology techniques to dissect molecular mechanisms of how viruses replicate and invade the host cell or its genome. One area of our major interest is retroviral integration, a critical step in the lifecycle of retroviruses that achieves permanent insertion of the reverse-transcribed viral genome into a host chromosome. We will build on our recent structural studies of the Human T-cell Leukemia virus and Rous sarcoma virus intasomes and further investigate the roles of host factors during integration of these retroviruses. Another area that we are pursuing is the replication of coronavirus RNA genomes and host cell invasion. In particular, we are interested in how a virally encoded exoribonuclease complex facilitates faithful replication of the large RNA genomes of coronaviruses, and how this unique proofreading activity could be modulated by small molecules. We are also investigating inhibition of the receptor binding of the coronavirus spike protein by novel antibodies and antibody-mimics. Overall, the studies proposed in this application will help better understand important RNA-based human pathogens and could aid in the development of antiviral strategies, or alternatively, gene delivery tools useful in research or gene therapy applications.