This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.
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