BK virus infection of the renal allograft has become a matter of considerable concern. We have played a leading role in defining the clinical course of these patients. Our effort in this area has been funded by an NIH sponsored RO-1 grant for the past 3 years. We have now prepared a competing continuation grant application to continue our study of this important problem.
Specific Aim # 1: To characterize the sequence diversity and phylogenetic evolution of BKV, and determine its potential impact on molecular diagnostic assays in clinical practice. We hypothesize that variant BKV strains are compromising our ability to (a) determine the true prevalence of viral infection, and (b) accurately quantitate the viral genomic load in clinical samples obtained from individual patients. It will be our goal to clarify the rate at which new viral strains are developing in nature, and to determine whether PCR-based diagnostic assays will also need to be continuously adapted to compensate for this continuing evolution.
Specific Aim # 2: To delineate host and viral factors that affect PV replication in the kidney. We propose to directly measure viral replication rates in mutant and wild type viruses in a cell culture system. In addition, we will determine if the risk of developing BK viruria and viremia is dependent on donor or host polymorphisms in genes capable of modulating host- pathogen interactions.
Specific Aim #3 : To examine the impact of smoldering BKV infections on the development of chronic allograft nephropathy. We hypothesize that asymptomatic viruria, which occurs in approximately 35% of our patients, represents a smoldering BKV infection that contributes to the development of chronic allograft nephropathy. To address this issue, we will use archival biopsy material to assess the serial progression of renal dysfunction in virus infected patients.
Specific Aim # 4: To use 3- dimensional homology modeling and virtual screening technology to discover anti-BKV drugs capable of binding functional domains on the VP-1 and T-antigen molecules. Given the growing importance of BKV infection in renal transplant recipients, there is a pressing need to develop anti-BKV drugs suitable for clinical use. We hypothesize that anti-BKV drugs can be discovered by screening chemical libraries for compounds that can bind to two key viral proteins, namely, viral capsid protein-1 (VP-1) and large T antigen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI051227-07
Application #
7787047
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Kehn, Patricia J
Project Start
2002-05-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
7
Fiscal Year
2010
Total Cost
$317,109
Indirect Cost
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Adam, B; Randhawa, P; Chan, S et al. (2014) Banff Initiative for Quality Assurance in Transplantation (BIFQUIT): reproducibility of polyomavirus immunohistochemistry in kidney allografts. Am J Transplant 14:2137-47
Masutani, Kosuke; Ninomiya, Toshiharu; Randhawa, Parmjeet (2013) HLA-A2, HLA-B44 and HLA-DR15 are associated with lower risk of BK viremia. Nephrol Dial Transplant 28:3119-26
Luo, Chunqing; Hirsch, Hans H; Kant, Jeffrey et al. (2012) VP-1 quasispecies in human infection with polyomavirus BK. J Med Virol 84:152-61
Masutani, Kosuke; Shapiro, Ron; Basu, Amit et al. (2012) Putative episodes of T-cell-mediated rejection in patients with sustained BK viruria but no viremia. Transplantation 94:43-9
Randhawa, Parmjeet; Mannon, Roslyn B (2012) A case of late kidney allograft failure: a clinical pathological conference from American Society of Nephrology Kidney Week 2011. Clin J Am Soc Nephrol 7:1884-9
Masutani, K; Shapiro, R; Basu, A et al. (2012) The Banff 2009 Working Proposal for polyomavirus nephropathy: a critical evaluation of its utility as a determinant of clinical outcome. Am J Transplant 12:907-18
Viscidi, Raphael P; Rollison, Dana E; Sondak, Vernon K et al. (2011) Age-specific seroprevalence of Merkel cell polyomavirus, BK virus, and JC virus. Clin Vaccine Immunol 18:1737-43
Randhawa, P; Kant, J; Shapiro, R et al. (2011) Impact of genomic sequence variability on quantitative PCR assays for diagnosis of polyomavirus BK infection. J Clin Microbiol 49:4072-6
Randhawa, Parmjeet S; Farasati, Noush A; Huang, Yuchen et al. (2010) Viral drug sensitivity testing using quantitative PCR: effect of tyrosine kinase inhibitors on polyomavirus BK replication. Am J Clin Pathol 134:916-20
Randhawa, Parmjeet S; Schonder, Kristine; Shapiro, Ron et al. (2010) Polyomavirus BK neutralizing activity in human immunoglobulin preparations. Transplantation 89:1462-5

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