Cellular Targets of the BKPyV miRNA

病毒编码多功能非结构蛋白，以适应尽可能多的编码 尽可能地将其转化为相对较小的基因组。这些蛋白质中的许多经常相互作用 用多种宿主细胞因子来操纵宿主环境，使其更有利于 例如，病毒复制和帮助病毒逃避免疫系统。各种病毒 也表达非编码RNA分子，如microRNAs(MiRNAs)，但这些分子的作用 人们对miRNAs的了解要少得多。顺理成章的是，就像非 结构蛋白，病毒将进化以最大限度地利用miRNAs。BK多瘤病毒 (BKPyV)是一种在人类人群中普遍存在的小型DNA病毒。在健康的个体中， 它在尿路中持续存在，不会引起明显的疾病，但在移植患者中， 不受控制的病毒复制会造成严重后果。BKPyV编码两个miRNA 前miRNA前体。这些miRNAs下调病毒肿瘤(T)抗原的表达， 通过刺激S阶段进入和招募促进病毒复制的多功能蛋白 病毒染色体的宿主DNA合成机器。这些miRNA不会影响 复制与疾病相关的遗传BKPyV变异，但严格限制复制 原型或野生型病毒，在人群中传播，并建立一种持久的 感染。在这个提议中，我们将检验这样的假设，即与它们的蛋白质对应物一样， MiRNAs是一种多功能大分子，也可以针对宿主因子来促进病毒 感染。这两个目标是确定东道主目标并开始评估这些目标的作用 在BKPyV感染中。

Viruses encode multifunctional non-structural proteins in order to accommodate as much coding potential as possible into their relatively small genomes. Many of these proteins often interact with multiple host cell factors to manipulate the host environment to make it more conducive to virus replication and to help the virus evade the immune system, for example. Various viruses also express non-coding RNA molecules such as microRNAs (miRNAs), but the roles of these miRNAs are much less well understood. It stands to reason that, as is the case for non- structural proteins, viruses would evolve to maximize the utility of the miRNAs. BK polyomavirus (BKPyV) is a small DNA virus that is ubiquitous in the human population. In healthy individuals, it persists in the urinary tract without causing obvious disease, but in transplant patients, uncontrolled virus replication has serious outcomes. BKPyV encodes two miRNAs from a single pre-miRNA precursor. These miRNAs downregulate expression of the viral tumor (T) antigens, multifunctional proteins that facilitate virus replication by stimulating S phase entry and recruiting the host DNA synthetic machinery to the viral chromosome. These miRNAs do not affect replication of disease-associated genetic BKPyV variants, but severely limit replication of the archetype, or wild type, virus that circulates through the population and establishes a persistent infection. In this proposal, we will test the hypothesis that like their protein counterparts, the miRNAs are multifunctional macromolecules that also target host factors to facilitate virus infection. The two aims are to identify host targets and begin to assess the role of those targets in BKPyV infection.