BK polyomavirus (BKPyV) is ubiquitous in the human population, with >80% seropositivity, and establishes a lifelong, subclinical, persistent infection of the urinary tract. Even during periodic episodes of replication in healthy individuals, as evidenced by excretion of virus into the urine, there are no clinical symptoms. In transplant patients, however, viral replication is associated with significant morbidity and can sometimes be fatal. The incidence of polyomavirus-associated nephropathy in renal transplant recipients and hemorrhagic cystitis in bone marrow transplant recipients has risen concomitant with rising numbers of transplants being performed and the development of more effective immunosuppressive drug regimens. Presently, there are no effective anti-viral treatments for BKPyV, 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 raises the risk of graft rejection, or relying on palliative care. There are two genetic forms of BKPyV, the archetype virus, which is the circulating form of the virus and can be isolated from urine of healthy persons and transplant recipients, and rearranged variants, which are almost exclusively isolated from transplant patients. Until recently, our understanding of BKPyV biology has been based on studies of rearranged variants, which can replicate in cell culture. Our laboratory's development of a system with which to study the archetype virus positions us to address important fundamental questions about persistence and reactivation, including how culturable replication variants arise.
The aims of this project are (1) to characterize the molecular mechanisms that regulate archetype viral replication, which is dependent on relative levels of expression of viral early genes and a virally-encoded miRNA; (2) to examine the genetic mechanisms leading to the rise of rearranged variants, which differ from the archetype virus in the DNA sequence of their non-coding control region; and (3) to establish a cell culture model for viral persistence, with which we will characterize the viral and cellular factors governing this process. The long term goals of these studies are to dissect the mechanisms that regulate BKPyV replication and to identify steps in the viral life cycle that may be amenable to the development of new antiviral drugs. Because all known polyomaviruses studied to date also exhibit a similar life style of persistence and reactivation, these studies have broad implications for the entire virus family.

Public Health Relevance

BK polyomavirus (BKPyV) is a pathogen that infects nearly all humans. In healthy people, it does not cause illness but in transplant patients who are being treated with drugs that suppress the immune system, virus replication can lead to severe disease. Unfortunately there are no effective drugs with which to treat these infections. The goal of this project is to understand the viral and cellular factors that control BKPyV replication, wit the ultimate aim of identifying possible new targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI060584-12
Application #
9384716
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Natarajan, Ramya
Project Start
2004-05-01
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
12
Fiscal Year
2018
Total Cost
Indirect Cost
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
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
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
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; Jiang, Mengxi (2015) What DNA viral genomic rearrangements tell us about persistence. J Virol 89:1948-50
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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