Epstein-Barr Virus (EBV) is a human tumor virus causally associated with multiple types of lymphomas and carcinomas. Its genome is maintained in both normal and malignant proliferating cells as a plasmid. We have studied EBV's plasmid replicon to elucidate both its synthesis and partitioning and its contributions to EBV's tumorigenesis. Earlier we identified its cis-acting element, oriP, and its sole viral trans-acting protein, EBNA1. We recently developed a method to visualize EBV plasmid replicons in live cells, which has uncovered several fascinating properties. For example, they are duplicated each S-phase only 84% of the time;and they encode a non-random mechanism of partitioning which spatially couples partitioning to their synthesis. We propose now in Aim 1 to characterize the synthesis and partitioning of EBV genomes early after infection of primary B-cells to understand how these events contribute to EBV's establishing its stable infection of these cells. We shall in Aim 2 dissect the mechanism of EBV's partitioning to understand its coupling to its synthesis. We have also recently discovered that inhibiting EBV's plasmid replicon by inhibiting EBNA1 induces apoptosis in normal and malignant, EBV-infected B-cells. We shall extend these findings in Aim 3 to EBV-associated tumors in immunocompromised hosts such as AIDS patients. In particular, we propose to investigate the mechanisms by which EBV prevents apoptosis in these infected, malignant B-cells and identify the viral genes that allow these tumor cells to survive.

Public Health Relevance

All of these studies will reveal the mechanisms by which EBV replicates as a plasmid in infected cells. In addition to indicating how inhibiting EBNA1 would be therapeutically beneficial, they should also identify additional targets for developing anti-viral anti-tumor drugs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA133027-05
Application #
8208237
Study Section
Special Emphasis Panel (ZRG1-IDM-M (02))
Program Officer
Daschner, Phillip J
Project Start
2008-04-23
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$291,367
Indirect Cost
$90,092
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Chiu, Ya-Fang; Sugden, Bill (2016) Epstein-Barr Virus: The Path from Latent to Productive Infection. Annu Rev Virol 3:359-372
Chakravorty, Adityarup; Sugden, Bill (2015) The AT-hook DNA binding ability of the Epstein Barr virus EBNA1 protein is necessary for the maintenance of viral genomes in latently infected cells. Virology 484:251-8
Kuzembayeva, Malika; Hayes, Mitchell; Sugden, Bill (2014) Multiple functions are mediated by the miRNAs of Epstein-Barr virus. Curr Opin Virol 7:61-5
Vereide, D T; Seto, E; Chiu, Y-F et al. (2014) Epstein-Barr virus maintains lymphomas via its miRNAs. Oncogene 33:1258-64
Shrestha, Prabha; Sugden, Bill (2014) Identification of properties of the Kaposi's sarcoma-associated herpesvirus latent origin of replication that are essential for the efficient establishment and maintenance of intact plasmids. J Virol 88:8490-503
Westhoff Smith, Danielle; Sugden, Bill (2013) Potential cellular functions of Epstein-Barr Nuclear Antigen 1 (EBNA1) of Epstein-Barr Virus. Viruses 5:226-40
Chiu, Ya-Fang; Sugden, Arthur U; Sugden, Bill (2013) Epstein-Barr viral productive amplification reprograms nuclear architecture, DNA replication, and histone deposition. Cell Host Microbe 14:607-18
Norby, Kathryn; Chiu, Ya-Fang; Sugden, Bill (2012) Monitoring plasmid replication in live mammalian cells over multiple generations by fluorescence microscopy. J Vis Exp :e4305
Kuzembayeva, Malika; Chiu, Ya-Fang; Sugden, Bill (2012) Comparing proteomics and RISC immunoprecipitations to identify targets of Epstein-Barr viral miRNAs. PLoS One 7:e47409
Vereide, David T; Sugden, Bill (2011) Lymphomas differ in their dependence on Epstein-Barr virus. Blood 117:1977-85

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