Grant: Project Grant

Epstein-Barr virus (EBV) infects most people worldwide, persists for a life-time and is a causative agent in several types of lymphoma, gastric carcinoma and nasopharyngeal carcinoma, accounting for 200,000 cancer cases per year. In addition, accumulating evidence has identified EBV infection as an important factor in the development of multiple sclerosis. EBV persists for our lifetime due to the ability to switch between latent and lytic modes on infection. Reactivation to lytic infection starts with expression of the EBV protein called BZLF1, which turns on several viral and some cellular genes. The resulting increase in viral levels, promotes infection of additional cell types that can lead to cancer. In addition, BZLF1 is found to be expressed in latent infections that occur in EBV-induced tumors, suggesting it has a direct role in oncogenesis. Using unbiased proteomics/genomics approaches, we have identified novel roles for BZLF1 in disrupting a cellular antiviral response and in inducing expression of a stem cell factor. In addition, we have identified cellular proteins that inhibit BZLF1 expression as well as mechanisms that EBV uses to ensure efficient BZLF1 expression in lytic infection. This project will determine how these BZLF1 regulators function, as well as the mechanisms and functional consequences of the roles we have discovered for BZLF1 in manipulating cellular proteins. This information will enable new approaches to inhibit EBV infection, thereby limiting the development of EBV-associated cancers and multiple sclerosis.