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 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 LMP2A message is the most readily detected EBV-specific message 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. Currently, studies designed to elucidate LMPA function in vitro are hampered by the need to use continuous cell lines or EBV transformed lymphoblastoid cell lines (LCLs) which do not reflect the unactivated B lymphocyte in which EBV is latent in the human host. To begin to understand the function of LMP2A in latent infection, we have developed a murine transgenic model system which targets LMP 2A expression to B lymphocytes thereby mimicking in vivo latent infection in humans. The model has proved useful in characterizing the alteration of normal B cell function by LMP2A and has proved invaluable in investigating the requirements for LMP2A function in latent infection. In the current proposal, we will continue our analysis of LMP2A function in our transgenic mice using both in vitro and in vivo techniques. An understanding of LMP2A function may provide insight for the development of novel therapeutics for the treatment or eradication of EBV latent infections in the human host, thereby preventing the development of AIDS-associated lymphoproliferative disease.
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