Parameters governing kidney cell infection with BKV

描述（由申请人提供）：多瘤病毒肾病（PVN）是肾移植患者中由人多瘤病毒（BKV）再激活引起的一种肾炎。BKV在大多数人群中普遍存在，并形成终身、亚临床、持续的肾脏感染。在移植患者和其他免疫功能低下的个体中，病毒复制导致组织损伤和肾功能障碍。近年来，随着移植数量的增加和旨在防止移植排斥反应的更有效的免疫抑制药物方案的发展，PVN的发病率急剧上升。目前，还没有针对BKV的有效抗病毒治疗方法，因此临床医生面临着减少免疫抑制药物剂量以使患者的免疫系统对抗病毒的困境，这增加了移植排斥的风险。BKV在人肾上皮细胞中的生物学特性正开始被揭示，更好的理解将对治疗方法的设计至关重要。利用体外细胞培养系统培养原代人肾近端小管上皮细胞，使其保持分化功能，可以研究BKV生命周期的关键特征。BKV在这些细胞中有效地复制。干扰素-？然而，抑制病毒基因的表达，从而抑制病毒的复制。该项目的目的是利用这个体外系统来表征调节病毒复制的机制，包括在复制和非复制条件下分析病毒染色质和病毒基因组的亚核定位。此外，还将研究病毒颗粒从质膜到达细胞核的途径，并在此过程中开始分解。这些研究的长期目标是剖析BKV在肾小管上皮细胞中复制的调控机制，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。

DESCRIPTION (provided by applicant): Polyomavirus nephropathy (PVN) is a form of nephritis caused by reactivation of the human polyomavirus, BKV, in renal transplant patients. BKV is ubiquitous in most human populations and establishes a lifelong, subclinical, persistent infection of the kidney. In transplant patients and other immunocompromised individuals, viral replication leads to tissue damage and renal dysfunction. The incidence of PVN has risen dramatically in recent years concomitant with rising numbers of transplants being performed and the development of more effective immunosuppressive drug regimens aimed towards preventing rejection of the transplant. Presently, there are no effective anti-viral treatments for BKV, 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 then raises the risk of graft rejection. The biology of BKV in human renal epithelial cells is beginning to be uncovered, and a better understanding will be critical in the design of therapeutic approaches. Using an in vitro cell culture system for the propagation of primary human renal proximal tubule epithelial cells that allows them to maintain their differentiated function, key features of the BKV life cycle can be studied. BKV replicates efficiently in these cells. Treatment of the cells with interferon-?, however, inhibits viral gene expression and, therefore, replication. The aims of this project are to utilize this in vitro system to characterize the mechanisms that regulate viral replication, including an analysis of viral chromatin and subnuclear localization of the viral genome under replicating and non- replicating conditions. In addition, the pathway that the viral particle takes from the plasma membrane to the nucleus of the cell, during which it begins to disassemble, will be examined. The long term goals of these studies are to dissect the mechanisms that regulate BKV replication in renal tubular epithelial cells and to identify steps in the viral life cycle that may be amenable to the development of new antiviral drugs. PUBLIC HEALTH RELEVANCE: BK virus is a virus that infects nearly everyone during early childhood but does not cause any disease in healthy individuals. However, in kidney transplant recipients the virus can reactivate from an otherwise dormant state and cause a destructive disease of the kidney. Up to ten percent of loss of function of transplanted kidneys is thought to be due to BK virus and there are no drugs available with which to treat the infection. BKV can also cause severe bladder disease in bone marrow transplant patients. Therefore, it is the goal of this project to understand more about how the virus infects cells in the kidney and urinary tract, which should lead to the identification of new targets for anti-viral drugs.