? 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. ? ?
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