Abstract

Epstein-Barr virus (EBV) is the cause of infectious mononucleosis and is also associated with Burkitt's lymphoma, Hodgkin's disease, a subset of gastric carcinomas, nasopharyngeal carcinoma, post-transplant lymphoproliferative disease and malignancies such as primary central nervous system lymphoma in AIDS patients. EBV is a ubiquitous virus that establishes a life-long latent infection in B cells and is associated B cell, T cell and epithelial cell malignancies. EBV has both latent and lytic phases to its life cycle. EBV latency genes are expressed in EBV associated malignancies. EBV lytic replication is required for virus spread from one individual to the next and is also a factor in maintenance of life-time infection within an individual. Regulation of latent and lytic EBV promoters has been studied extensively in reporter assays and in EBV immortalized B cell lines in culture. However, the biology of EBV infection of the epithelial cell and the conditions that favor a latent versus a lytic outcome are poorly understood. The recent availability of recombinant EBV expressing GFP and drug selection markers, new epithelial cell lines and improved sources of infectious virus now make it feasible to address the parameters that regulate the outcome of EBV infection of epithelial cells. With regards to B cell infection, integrating the data acquired on EBV promoter regulation in B cell lines with in vivo EBV biology has been handicapped by a lack of accessible animal models.
The Specific Aims of this application address these issues and are:
Aim 1. To identify conditions that favor latent versus lytic EBV infection in epithelial cells using GFP expressing EBV virus and immortalized epithelial cell lines.
Aim 2. To evaluate the contribution of the BART encoded RPMS protein to establishment of infection and lytic DNA replication. RPMS interactors identified in a yeast two-hybrid screen will provide experimental direction for the studies.
Aim 3. To develop a mouse model for in vivo evaluation of EBV promoter expression using hematopoietic reconstitution with lentiviral transduced stem cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA030356-28
Application #
7568205
Study Section
Virology - A Study Section (VIRA)
Program Officer
Daschner, Phillip J
Project Start
1981-09-30
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2011-02-28
Support Year
28
Fiscal Year
2009
Total Cost
$330,440
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001910777
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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