Poxviral antagonism of the IFIT-mediated antiviral response

描述（由申请人提供）：许多干扰素刺激基因（isg）和其他抗病毒机制保护人类免受多种病毒的侵害。从病毒的角度来看，许多isg代表了病毒复制的强大障碍。因此，为了在进化上取得成功，病毒必须找到逃避宿主抗病毒机制的方法。事实上，多种病毒编码特定的因子，使它们能够直接对抗宿主的抗病毒蛋白。因此，这种病毒拮抗剂的鉴定和表征对于了解人类对病毒的易感性以及设计新的疗法和疫苗具有高度相关性。尽管这在生物医学上具有重要意义，但识别新的病毒拮抗剂甚至是哪些宿主基因被病毒拮抗一直很困难。我们之前的进化引导功能研究表明，已知的宿主基因的病毒拮抗作用通常与宿主基因的快速适应性进化或正选择相关。本应用旨在通过提出阳性选择分析可用于预测哪些宿主抗病毒蛋白被未知病毒拮抗剂靶向，并能够识别以前未知的拮抗剂，从而极大地扩展这一概念的实用性。我们将重点关注IFIT（干扰素诱导的四肽重复）基因家族，这是一组高度干扰素诱导的广泛作用的抗病毒因子，对宿主防御几种病毒很重要。IFIT基因没有已知的病毒拮抗剂。然而，它们中的一些是在强烈的正选择下进化的，这使我们假设病毒已经用拮抗剂反复靶向它们。我们将结合进化遗传学、生物化学和病毒学技术，测试IFIT蛋白是否是病毒拮抗的直接靶点。这些研究将确定IFIT蛋白与病毒拮抗剂之间的生化和功能相互作用，并测试IFIT拮抗剂对病毒复制的重要性。进一步的实验将检验IFIT进化的功能后果，以及这是否定义了IFIT蛋白对当前流行病毒拮抗的易感性。最后，实验进化将揭示病毒对抗ifit介导的宿主防御的进化路径。这些研究不仅揭示了拮抗剂在病毒逃避IFIT介导的抗病毒反应中所起的作用，而且还代表了一种潜在的广泛适用的策略，用于新的鉴定和表征重要抗病毒基因的病毒拮抗剂。

DESCRIPTION (provided by applicant): Many interferon-stimulated genes (ISGs) and other antiviral mechanisms protect humans from a large variety of viruses. Taken from a viral perspective, many ISGs represent potent barriers to viral replication. Therefore, to be evolutionarily successful, viruses must find ways to evade these host antiviral mechanisms. Indeed, multiple viruses encode specific factors that allow them to directly antagonize host antiviral proteins. The identification and characterization of such viral antagonists is thus highl relevant for understanding human susceptibility to viruses and designing new therapies and vaccines. Despite this great biomedical importance, identifying novel viral antagonists or even which host genes are antagonized by viruses has been difficult. Our previous evolution-guided functional studies have revealed that known viral antagonism of a host gene is often correlated with rapid adaptive evolution, or positive selection, in that host gene. This application seeks to greatly expand the utility of this concept by proposing that positive selection analyses can be used to predict which host antiviral proteins are targeted by unknown viral antagonists and enable identification of the previously unknown antagonists. We will focus on the IFIT (Interferon-induced with tetratricopeptide repeat) gene family, a highly interferon-induced set of broadly-acting antiviral factors that are important for host defense against several viruses. IFIT genes have no known viral antagonists. However several of them have evolved under strong positive selection, leading us to hypothesize that viruses have repeated targeted them with antagonists. We will test whether IFIT proteins are direct targets of viral antagonism by employing a combination of insights gleaned from evolutionary genetics, together with biochemistry and virology techniques. These studies will define the biochemical and functional interactions between IFIT proteins and viral antagonists and test the importance of IFIT antagonism for viral replication. Additional experiments will examine the functional consequences of IFIT evolution, and whether this defines the susceptibility of IFIT proteins to antagonism by currently circulating viruses. Finally, experimental evolution will reveal the evolutionary path that viruses take to counteract IFIT-mediated host defenses. These studies will not only shed light on the role that antagonists play in viral evasion of the IFIT- mediated antiviral response, but will also represent a potentially widely applicable strategy for the de nov identification and characterization of viral antagonists of important antiviral genes.