Parameters governing kidney cell infection with BKV

描述(申请人提供)：多瘤病毒肾病(PVN)是一种由肾移植患者中人类多瘤病毒BKV重新激活而引起的肾炎。BKV在大多数人群中普遍存在，并建立了一种终生的、亚临床的、持续性的肾脏感染。在移植患者和其他免疫功能受损的人中，病毒复制会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预防移植排斥反应的更有效的免疫抑制药物方案的开发，PVN的发病率急剧上升。目前，BKV还没有有效的抗病毒治疗方法，因此临床医生面临着减少免疫抑制药物的剂量以使患者的免疫系统与病毒作斗争的两难境地，这将增加移植排斥反应的风险。BKV在人肾上皮细胞中的生物学开始被发现，更好的理解将在治疗方法的设计中至关重要。使用体外细胞培养系统对原代人肾近端小管上皮细胞进行增殖，使其保持分化功能，可以研究BKV生活史的关键特征。BKV在这些细胞中高效复制。然而，用干扰素处理细胞会抑制病毒基因的表达，从而抑制病毒的复制。这个项目的目的是利用这个体外系统来描述调控病毒复制的机制，包括分析病毒染色质和病毒基因组在复制和非复制条件下的亚核定位。此外，还将检查病毒颗粒从质膜到细胞核的路径，在此期间它开始分解。这些研究的长期目标是剖析调节肾小管上皮细胞中BKV复制的机制，并确定病毒生命周期中可能适合于新的抗病毒药物开发的步骤。

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.