? With the introduction of immunosuppressive drugs such as tacrolimus and mycophenolate mofetil, the incidence of acute rejection in renal transplantation has fallen to <10% at some major medical centers. Unfortunately, these intensive therapeutic regimens increase the risk for viral infections. Of particular concern is the recent emergence of polyomavirus allograft nephropathy (PVAN) in approximately 5% of patients. PVAN is an inadequately studied and distressing condition that frequently leads to graft loss. Since polyomavirus (PV) is latent in the kidneys of up to 50% of healthy adults, it is likely that milder forms of PV associated graft dysfunction go unrecognized and untreated, leading to ongoing graft damage and accelerated development of chronic rejection.
The specific aims of this proposal are (1) To characterize the complete clinical spectrum of PV infection; (2) To delineate the host and viral factors that affect PV replication in man; (3) To analyze PV infection-associated cellular gene expression in cultured cells, blood and urine of kidney transplant patients, and tissue specimens with urogenital carcinoma; and (4) To perform in-vitro testing of anti-BK virus drugs for possible future use in the clinical arena.
These specific aims will be accomplished by (a) Performing PCR for polyomaviruses BK, JC, and SV40 in clinical samples, (b) Nucleotide sequencing to assign viral genotypes and characterize genetic mutations and rearrangements in the viral genome, (c) Using DNA microarray technology, RT-PCR, and ELISA to characterize virus induced host gene expression, and (d) Testing the effect of putative anti-viral drugs in a flow cytometric assay designed to measure the rate of viral replication in cultured cells. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI051227-03
Application #
6844319
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Kehn, Patricia J
Project Start
2003-07-01
Project End
2006-12-31
Budget Start
2005-01-01
Budget End
2006-12-31
Support Year
3
Fiscal Year
2005
Total Cost
$259,875
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
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
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
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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