Parameters governing infection with BK polyomavirus

 描述（由申请人提供）：BK多瘤病毒（BKPyV）在人群中普遍存在，血清阳性率>80%，并建立终身、亚临床、持续感染 泌尿道的问题即使在健康个体的周期性复制期间，如通过将病毒排泄到尿液中所证明的，也没有临床症状。然而，在移植患者中，病毒复制与显著的发病率相关，有时可能是致命的。肾移植受者中多瘤病毒相关肾病和骨髓移植受者中出血性膀胱炎的发病率随着移植数量的增加和更有效的免疫抑制药物方案的开发而增加。目前，对于BKPyV没有有效的抗病毒治疗，因此临床医生面临着减少免疫抑制药物的剂量以允许患者的免疫系统对抗病毒的困境，这增加了移植物排斥的风险，或者依赖姑息治疗。BKPyV有两种遗传形式，原型病毒，它是病毒的循环形式，可以从健康人和移植受体的尿液中分离出来，以及重排变体，几乎完全从移植患者中分离出来。直到最近，我们对BKPyV生物学的理解一直基于对重排变体的研究，这些变体可以在细胞培养中复制。我们实验室开发的研究原型病毒的系统使我们能够解决有关持久性和再激活的重要基本问题，包括如何产生可培养的复制变体。本项目的目的是：（1）表征调控原型病毒复制的分子机制，其依赖于病毒早期基因和病毒编码的miRNA的相对表达水平;（2）检查导致重排变体出现的遗传机制，其不同于原型病毒的非编码控制区的DNA序列;（3）建立病毒持续存在的细胞培养模型，并对影响病毒持续存在的病毒和细胞因素进行分析。这些研究的长期目标是剖析调节BKPyV复制的机制，并确定病毒生命周期中可能适合开发新的抗病毒药物的步骤。由于迄今为止研究的所有已知多瘤病毒也表现出类似的持续和再激活的生活方式，因此这些研究具有广泛的意义 对整个病毒家族来说。

 DESCRIPTION (provided by applicant): BK polyomavirus (BKPyV) is ubiquitous in the human population, with >80% seropositivity, and establishes a lifelong, subclinical, persistent infection of the urinary tract. Even during periodic episodes of replication in healthy individuals, as evidenced by excretion of virus into the urine, there are no clinical symptoms. In transplant patients, however, viral replication is associated with significant morbidity and can sometimes be fatal. The incidence of polyomavirus-associated nephropathy in renal transplant recipients and hemorrhagic cystitis in bone marrow transplant recipients has risen concomitant with rising numbers of transplants being performed and the development of more effective immunosuppressive drug regimens. Presently, there are no effective anti-viral treatments for BKPyV, and therefore the clinician is faced with the dilemma of reducing the dose of immunosuppressive drugs to allow the patient's immune system to battle the virus, which raises the risk of graft rejection, or relying on palliative care. There are two genetic forms of BKPyV, the archetype virus, which is the circulating form of the virus and can be isolated from urine of healthy persons and transplant recipients, and rearranged variants, which are almost exclusively isolated from transplant patients. Until recently, our understanding of BKPyV biology has been based on studies of rearranged variants, which can replicate in cell culture. Our laboratory's development of a system with which to study the archetype virus positions us to address important fundamental questions about persistence and reactivation, including how culturable replication variants arise. The aims of this project are (1) to characterize the molecular mechanisms that regulate archetype viral replication, which is dependent on relative levels of expression of viral early genes and a virally-encoded miRNA; (2) to examine the genetic mechanisms leading to the rise of rearranged variants, which differ from the archetype virus in the DNA sequence of their non-coding control region; and (3) to establish a cell culture model for viral persistence, with which we will characterize the viral and cellular factors governing this process. The long term goals of these studies are to dissect the mechanisms that regulate BKPyV replication and to identify steps in the viral life cycle that may be amenable to the development of new antiviral drugs. Because all known polyomaviruses studied to date also exhibit a similar life style of persistence and reactivation, these studies have broad implications for the entire virus family.