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 rising numbers of transplants being performed and 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 to allow the patient's immune system to battle the virus, which then raises the risk of graft rejection. The biology of BKV in human renal epithelial cells is beginning to be uncovered, and a better understanding will be critical in the design of therapeutic approaches. Using an in vitro cell culture system for the propagation of primary human renal proximal tubule epithelial cells that allows them to maintain their differentiated function, key features of the BKV life cycle can be studied. BKV replicates efficiently in these cells. Treatment of the cells with interferon-?, however, inhibits viral gene expression and, therefore, replication.
The aims of this project are to utilize this in vitro system to characterize the mechanisms that regulate viral replication, including an analysis of viral chromatin and subnuclear localization of the viral genome under replicating and non- replicating conditions. In addition, the pathway that the viral particle takes from the plasma membrane to the nucleus of the cell, during which it begins to disassemble, will be examined. The long term goals of these studies are to dissect the mechanisms that regulate BKV replication in renal tubular epithelial cells and to identify steps in the viral life cycle that may be amenable to the development of new antiviral drugs.

Public Health Relevance

BK virus is a virus that infects nearly everyone during early childhood but does not cause any disease in healthy individuals. However, in kidney transplant recipients the virus can reactivate from an otherwise dormant state and cause a destructive disease of the kidney. Up to ten percent of loss of function of transplanted kidneys is thought to be due to BK virus and there are no drugs available with which to treat the infection. BKV can also cause severe bladder disease in bone marrow transplant patients. Therefore, it is the goal of this project to understand more about how the virus infects cells in the kidney and urinary tract, which should lead to the identification of new targets for anti-viral drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI060584-09
Application #
8521888
Study Section
Virology - B Study Section (VIRB)
Program Officer
Park, Eun-Chung
Project Start
2004-05-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
9
Fiscal Year
2013
Total Cost
$320,514
Indirect Cost
$111,129
Name
University of Michigan Ann Arbor
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zhao, Linbo; Marciano, Anthony T; Rivet, Courtney R et al. (2016) Caveolin- and clathrin-independent entry of BKPyV into primary human proximal tubule epithelial cells. Virology 492:66-72
Justice, Joshua L; Verhalen, Brandy; Kumar, Ranjit et al. (2015) Quantitative Proteomic Analysis of Enriched Nuclear Fractions from BK Polyomavirus-Infected Primary Renal Proximal Tubule Epithelial Cells. J Proteome Res 14:4413-24
Verhalen, Brandy; Justice, Joshua L; Imperiale, Michael J et al. (2015) Viral DNA replication-dependent DNA damage response activation during BK polyomavirus infection. J Virol 89:5032-9
Imperiale, Michael J; Jiang, Mengxi (2015) What DNA viral genomic rearrangements tell us about persistence. J Virol 89:1948-50
Bennett, Shauna M; Zhao, Linbo; Bosard, Catherine et al. (2015) Role of a nuclear localization signal on the minor capsid proteins VP2 and VP3 in BKPyV nuclear entry. Virology 474:110-6
Imperiale, Michael J (2014) Polyomavirus miRNAs: the beginning. Curr Opin Virol 7:29-32
Broekema, Nicole M; Imperiale, Michael J (2013) miRNA regulation of BK polyomavirus replication during early infection. Proc Natl Acad Sci U S A 110:8200-5
Bennett, Shauna M; Jiang, Mengxi; Imperiale, Michael J (2013) Role of cell-type-specific endoplasmic reticulum-associated degradation in polyomavirus trafficking. J Virol 87:8843-52
Jiang, Mengxi; Imperiale, Michael J (2012) Design stars: how small DNA viruses remodel the host nucleus. Future Virol 7:445-459
Bennett, Shauna M; Broekema, Nicole M; Imperiale, Michael J (2012) BK polyomavirus: emerging pathogen. Microbes Infect 14:672-83

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