: The overall goal of our research is to better understand the pathogenesis of Epstein-Barr virus (EBV) infection in order to develop therapies that can reduce, control, or prevent EBV-associated diseases. EBNA-1 is an EBV protein important for the maintenance of the virus episome. EBNA-1 is expressed in all phases of EBV infection, is one of only a few viral genes expressed by infected B cells circulating in the blood of persistently infected hosts, and is the gene most consistently expressed in EBV associated malignancies. EBNA-1 specific cytotoxic T cells are present in persistently EBV infected individuals, but these T cells are unable to effectively kill EBV infected cells due in part to an inhibitory effect of the EBNA-1 glycine-alanine repeat (GAR) domain that prevents appropriate processing and presentation of EBNA-1 peptides to T cells. This application focuses on the importance of EBNA-1 for persistent EBV infection, the importance of EBNA-1 immune evasion for persistent infection, and the possibility of manipulating the EBNA-1 immune response as a therapeutic tool against EBV-associated malignancies. We will use the rhesus lymphocryptovirus (LCV) animal model system for EBV pathogenesis and other laboratory systems to address these issues in the following specific aims: ? Specific Aim #1. Test whether the ability to downregulate LCV latent gene expression to an EBNA- 1 only promoter is essential for persistent LCV infection. ? Specific Aim #2. Test whether immune evasion mediated by the EBNA-1 glycine-alanine repeat domain is essential for persistent LCV infection. ? Specific Aim #3. Use immunosuppression to test whether the EBNA-1 mutant viruses are attenuated due to more effective immune clearance versus a functional defect required for persistent infection. ? Specific Aim #4. Explore strategies to enhance EBNA-1 recognition and killing of EBV infected B cells by EBNA-1 specific CTLs as a potential therapeutic. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA068051-12
Application #
7250199
Study Section
Virology - B Study Section (VIRB)
Program Officer
Daschner, Phillip J
Project Start
1995-07-01
Project End
2010-04-30
Budget Start
2007-05-14
Budget End
2008-04-30
Support Year
12
Fiscal Year
2007
Total Cost
$403,843
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Mühe, Janine; Wang, Fred (2015) Host Range Restriction of Epstein-Barr Virus and Related Lymphocryptoviruses. J Virol 89:9133-6
Griffin, Bryan D; Gram, Anna M; Mulder, Arend et al. (2013) EBV BILF1 evolved to downregulate cell surface display of a wide range of HLA class I molecules through their cytoplasmic tail. J Immunol 190:1672-84
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Kawabata, Thomas; Weaver, James; Thomas, Dolca et al. (2012) Summary of roundtable discussion meeting: non-human primates to assess risk for EBV-related lymphomas in humans. J Immunotoxicol 9:121-7
Ohashi, Makoto; Orlova, Nina; Quink, Carol et al. (2011) Cloning of the Epstein-Barr virus-related rhesus lymphocryptovirus as a bacterial artificial chromosome: a loss-of-function mutation of the rhBARF1 immune evasion gene. J Virol 85:1330-9
Fogg, Mark H; Wirth, Lori J; Posner, Marshall et al. (2009) Decreased EBNA-1-specific CD8+ T cells in patients with Epstein-Barr virus-associated nasopharyngeal carcinoma. Proc Natl Acad Sci U S A 106:3318-23
Rivailler, Pierre; Kaur, Amitinder; Johnson, R Paul et al. (2006) Genomic sequence of rhesus cytomegalovirus 180.92: insights into the coding potential of rhesus cytomegalovirus. J Virol 80:4179-82

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