Abstract

Epstein-Barr virus (EBV) immortalizes B cells and is associated with human malignancies including Burkitt's lymphoma, nasopharyngeal carcinoma, gastric carcinoma, Hodgkin's disease and lymphoproliferative disease in immunosuppressed patients such as AIDS patients and organ and bone marrow transplant patients. Primary infection by EBV may cause infectious mononucleosis in young adults. Primary infection leads to a proliferative expansion of the infected B cells. This is followed by the establishment of life-long persistence in which the EBV genome resides in resting B cells. Lytic viral replication occurs in the oropharynx and results in virus shedding into the saliva. Different patterns of EBV latency gene expression are seen in latently infected resting B cells and in EBV associated tumors. This application addresses factors that may regulate these expression patterns and contribute to the different aspects of EBV pathogenesis. EBV replication is necessary for virus spread and Zta is a key regulator of the EBV lytic cycle. Zta not only regulates EBV lytic DNA replication but may also influence the maintainance of latent infection.
The Specific Aims are:
(Aim 1). To characterize the role of Zta in replication of the EBV origin of lytic replication, orilyt. Transfection assays will be used to analyse the role of Zta in the formation of replication compartments, to analyze the relative contributions of Zta's transcriptional and replication activities to orilyt activation and to relate Zta mediated regulation of the cell cycle to Zta replication function.
(Aim 2). To evaluate the contribution of the JAK-STAT signaling pathway to the regulation of EBV latency gene expression in in vivo latency and tumorigenesis. STAT regulation of individual EBV latency promoters will be examined in transient assays. The role of activated STATs and Zta expression in the maintainance of EBV positive epithelial tumor cell lines in culture will be pursued and negative regulation of the EBV lytic cycle by STATs will be examined.
(Aim 3). A role for EBNA-1 in the regulation of EBV latency gene expression will be evaluated.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA030356-20
Application #
6375638
Study Section
Virology Study Section (VR)
Program Officer
Daschner, Phillip J
Project Start
1981-09-30
Project End
2005-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
20
Fiscal Year
2001
Total Cost
$294,525
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Zheng, Dasheng; Wan, Jun; Cho, Yong Gu et al. (2011) Comparison of humoral immune responses to Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus using a viral proteome microarray. J Infect Dis 204:1683-91
Li, Renfeng; Zhu, Jian; Xie, Zhi et al. (2011) Conserved herpesvirus kinases target the DNA damage response pathway and TIP60 histone acetyltransferase to promote virus replication. Cell Host Microbe 10:390-400
Zhu, Jian; Liao, Gangling; Shan, Liang et al. (2009) Protein array identification of substrates of the Epstein-Barr virus protein kinase BGLF4. J Virol 83:5219-31
Lo, Angela Kwok Fung; To, Ka Fai; Lo, Kwok Wai et al. (2007) Modulation of LMP1 protein expression by EBV-encoded microRNAs. Proc Natl Acad Sci U S A 104:16164-9
Huang, Jian; Liao, Gangling; Chen, Honglin et al. (2006) Contribution of C/EBP proteins to Epstein-Barr virus lytic gene expression and replication in epithelial cells. J Virol 80:1098-109
Liao, Gangling; Huang, Jian; Fixman, Elizabeth D et al. (2005) The Epstein-Barr virus replication protein BBLF2/3 provides an origin-tethering function through interaction with the zinc finger DNA binding protein ZBRK1 and the KAP-1 corepressor. J Virol 79:245-56
Chen, Honglin; Huang, Jian; Wu, Frederick Y et al. (2005) Regulation of expression of the Epstein-Barr virus BamHI-A rightward transcripts. J Virol 79:1724-33
Wu, Frederick Y; Wang, Shizhen Emily; Chen, Honglin et al. (2004) CCAAT/enhancer binding protein alpha binds to the Epstein-Barr virus (EBV) ZTA protein through oligomeric interactions and contributes to cooperative transcriptional activation of the ZTA promoter through direct binding to the ZII and ZIIIB motifs during J Virol 78:4847-65
Chen, Honglin; Hutt-Fletcher, Lindsey; Cao, Liang et al. (2003) A positive autoregulatory loop of LMP1 expression and STAT activation in epithelial cells latently infected with Epstein-Barr virus. J Virol 77:4139-48
Wu, Frederick Y; Chen, Honglin; Wang, Shizhen Emily et al. (2003) CCAAT/enhancer binding protein alpha interacts with ZTA and mediates ZTA-induced p21(CIP-1) accumulation and G(1) cell cycle arrest during the Epstein-Barr virus lytic cycle. J Virol 77:1481-500

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