Epstein-Barr virus (EBV) causes infectious mononucleosis in adolescents and malignant 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. Besides EBNA1, which is required for episome maintenance, LMP1, LMP2A, and LMP2B are the latently expressed proteins consistently detected in EBV related malignancies, and the EBNA1 and LMP2A messages are the only EBV-specific messages detected in PCR analysis of B lymphocytes from individuals harboring latent EBV infections. 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. The elucidation of LMP2A function in in vitro latent infection utilizing biochemical and genetic techniques will be the focus of this research proposal. The following aims are proposed: 1) Investigate the roles of the Src family protein tyrosine kinase (PTK) Lyn, the B cell Syk PTK, and LMP2B in the regulation of EBV latency. 2) Identify LMP2A associated proteins in B lymphocytes. 3) Recombine LMP2A site specific mutations into the EBV genome. 4) Investigate the properties of LCLs transformed and latently infected with the LMP2A mutant viruses.
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