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.
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