Epstein-Barr virus (EBV) causes infectious mononucleosis in adolescents and malignant B lymphocyte proliferation in AIDS patients and patients undergoing immune suppression for organ transplantation. EBV is etiologically associated with African Burkitt's lymphoma and nasopharyngeal carcinoma. In vitro, EBV transformed, latently infected B lymphocytes contain EBV episomes and express nine virus-encoded proteins. Six are nuclear proteins (EBNAs) and three are the integral membrane proteins, LMP1, LMP2A, and LMP2B. These nine proteins are presumed to mediate latent virus infection or B lymphocyte proliferation and thus are under intense investigation. LMP2A is the most consistently detected protein in B lymphocytes from normal individuals with EBV latent infections and along with EBNA1 and LMP1 are consistently detected in EBV-associated malignancies. Our previous studies have shown that LMP2A is essential for down modulation of cell surface receptor mediated signal transduction in B lymphocytes infected with EBV. By down modulating cell surface signal transduction, LMP2A is important for maintaining EBV latent infection in vitro. We have shown that LMP2A functional mimics a B cell receptor by associating with the Syk protein tyrosine kinase (PTK) and the Src family PTKs. LMP2A associates with Nedd4-family ubiquitin ligases resulting in the ubiquitination of LMP2A-associated Lyn and Syk PTKs. The elucidation of LMP2A function in in vitro latent infection utilizing biochemical and genetic techniques will be the focus of this research proposal. An understanding of LMP2A function may provide insight for the development of novel therapeutics for the treatment of EBV-related malignancies in AIDS patients as well as immunocompetent individuals harboring EBV latent infections. The following aims are proposed: 1) Investigate LMP2A targeting to lipid rafts and the role of lipid raft constituents in LMP2A function. 2) Investigate trafficking of LMP2A and LMP2A-associated proteins. 3) Investigate the importance of ubiquitination and role of Nedd4-family ubiqutin ligases in LMP2A function. 4) Investigate the properties of LCLs transformed and latently infected with the LMP2A mutant viruses.
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