Parameters Governing Kidney Cell Infection with BKV

描述（由申请方提供）：多瘤病毒肾病（PVN）是肾移植患者中人多瘤病毒BKV再活化引起的一种肾炎。 BKV在大多数人群中普遍存在，并造成终身、亚临床、持续性肾脏感染。 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，对于BKV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，这随后增加了排斥的风险。 BKV的生物学尚不清楚，特别是在人肾上皮细胞中。 这样的理解将是至关重要的治疗方法的合理设计。 使用体外细胞培养系统繁殖原代人近端小管上皮（HPTE）细胞，使它们能够保持其分化的功能，可以详细研究BKV的生命周期。 初步结果表明，BKV在这些细胞中有效地复制，从而重现了免疫抑制患者的情况。 该项目的长期目标是利用这种体外系统来表征病毒生命周期的细节，并确定防止病毒复制的条件，这些条件类似于病毒在健康宿主中会遇到的条件。 将对病毒基因表达进行详细研究。 此外，病毒和宿主细胞之间的相互作用的彻底分析，重点是在调节感染的趋化因子和细胞因子的作用，将进行。 这些体外研究的结果将与密歇根大学医院接受肾移植患者的活检检查相关，以确认体外观察结果模拟患者发生的事件。 拟议研究的结果将大大提高我们对BKV在缺乏功能性免疫系统的情况下重新激活的机制的认识，因此为更好的治疗方式指明了方向。

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 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 so as to allow the patient's immune system to battle the virus, which then raises the risk of rejection. The biology of BKV is not well understood, particularly in human kidney epithelial cells. Such an understanding will be critical in the rational design of therapeutic approaches. Using an in vitro cell culture system for the propagation of primary human proximal tubule epithelial (HPTE) cells, which allows them to maintain their differentiated function, the life cycle of BKV can be studied in detail. Preliminary results indicate that BKV replicates efficiently in these cells, thereby reproducing the situation in the immunosuppressed patient. The long-term aims of this project are to utilize this in vitro system to characterize the details of the viral life cycle and to define conditions that will prevent viral replication similar to those the virus would encounter in a healthy host. A detailed investigation of viral gene expression will be performed. In addition, a thorough analysis of the interactions between the virus and the host cell, focusing on the role of chemokines and cytokines in modulating the infection, will be undertaken. The findings from these in vitro studies will be correlated with an examination of biopsies obtained from patients undergoing renal transplantation at the University of Michigan Hospital to confirm that the in vitro observations mimic the events that occur in the patient. The results of the proposed studies will greatly enhance our knowledge of the mechanism by which BKV is reactivated in the absence of a functioning immune system and therefore point the way to better treatment modalities.