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，随着旨在预防移植排斥反应的更有效的免疫抑制药物方案的发展，PVN的发生率急剧上升。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剂量的两难境地，以使患者的免疫系统与病毒作斗争，从而增加排斥反应的风险。BKV的生物学还不是很清楚，特别是在人的肾上皮细胞中。这样的理解对合理设计治疗方法至关重要。利用体外细胞培养系统对原代培养的人近端小管上皮细胞(HPTE)进行增殖，使其保持分化功能，可以详细研究BKV的生活史。初步结果表明，BKV在这些细胞中有效复制，从而重现免疫抑制患者的情况。该项目的长期目标是利用这一体外系统来描述病毒生命周期的细节，并确定防止病毒复制的条件，类似于病毒在健康宿主中遇到的情况。将对病毒基因的表达进行详细的调查。此外，还将对病毒和宿主细胞之间的相互作用进行彻底的分析，重点是趋化因子和细胞因子在调节感染中的作用。这些体外研究的结果将与密歇根大学医院接受肾移植的患者的活检组织检查相关联，以确认体外观察模拟了患者体内发生的事件。拟议的研究结果将极大地提高我们对BKV在缺乏正常运作的免疫系统的情况下被重新激活的机制的了解，从而为更好的治疗方式指明方向。

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.