BK Virus (BKV), a member of the polyomavirus family, is a ubiquitous pathogen of humans, infecting virtually 100% of most populations during early childhood. In healthy individuals, the virus establishes a lifelong, subclinical infection of the urinary tract. The virus can reactivate in immunocompromised persons, particularly recipients of renal and bone marrow transplants, leading to severe disease in the kidney or urinary bladder. It has been known for many years that the primate polyomaviruses, BKV, JCV, and SV40, can induce tumors in experimental animals, either by direct infection or in the context of transgenic animals. The primate viruses encode two oncoproteins, large T antigen and small t antigen, that deregulate cell growth control. Recently, a number of reports have associated BKV with various human cancers, including those of the urinary tract. The long term goal of this project is to determine whether BKV plays a role in the etiology of prostate cancer. Mutations in the retinoblastoma susceptibility (RB1) and p53 genes occur rarely or late, respectively, during prostate cancer progression, indicating that a virus which interferes with these critical tumor suppressor pathways may play a role during the early stages of carcinogenesis. BKV has been detected in normal and abnormal prostate epithelium, and large T antigen is expressed in the abnormal cells. The large T antigen in these cells is found in the cytoplasm rather than its normal location, the nucleus, indicating that the virus is not undergoing lytic replication. Moreover, p53 co-localizes with large T antigen, indicating that it is not functioning as a tumor suppressor. The frequency of detection of large T antigen in normal prostates is significantly lower than that in cancerous prostates. The aims of this proposal are to continue a molecular analysis of both normal and cancerous prostates with respect to the virus and key host proteins, to analyze the biology of virus strains cloned from tumor samples, and to understand how large T antigen is sequestered in the cytoplasm of prostate epithelial cells and the effects of cytoplasmic large T antigen on the cell. Together these studies will allow a better determination of whether BKV plays a role in prostate cancer and will advance our understanding of the biology of BKV. If a role for BKV in prostate cancer exists, there is the possibility of developing therapeutics or vaccines that are specific for the virus, thereby reducing the morbidity, mortality, and even the incidence of this cancer.