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Epstein-Barr virus (EBV) is a human herpesvirus which causes mononucleosis and is also associated with malignancies including lymphoproliferative disease in patients with AIDS. EBV infects B lymphocytes and growth transforms these cells so that they proliferate indefinitely in vitro. In these transformed cells, EBV expresses eleven genes. One of these genes encodes latent infection membrane protein 1 (LMP1), an integral plasma membrane protein. Considerable evidence indicates that LMP1 plays a critical role in EBV mediated B lymphocyte transformation and EBV associated malignancy. When expressed in EBV negative B lymphoma cells, LMP1 causes induction of B lymphocyte activation markers, the bcl 2 proto oncogene and NF-kappaB similar to changes seen in EBV transformed B-cells. LMP1 is expressed in a number of human malignancies including lymphoproliferative disease in AIDS patients, Hodgkin's disease and nasopharyngeal carcinoma, suggesting it plays an important role in such disease. LMP1 is essential for EBV mediated B lymphocyte transformation since EBV lacking LMP1 cannot immortalize B cells. Recent work has demonstrated that the 192 amino acid carboxy terminal region of LMP1 is essential for its function since recombinant EBV with LMP1 deleted for this region cannot immortalize B lymphocytes.

The first goal of this project is to determine the specific domains of the LMP1 carboxy terminus that are essential for LMP1 transforming function. Extensive EBV recombinant molecular genetic analysis will be done to determine domains of the LMP1 carboxy terminus that are essential for B lymphocyte transformation (immortalization). LMP1 mutations that result in EBVs that cannot transform B cells will identify critical functional regions. The second goal of this project is to assay the phenotype of the LMP1 mutations. Induction of B cell surface markers, the bcl 2 proto- oncogene, NF-kappaB activity and tumorigenicity in SCID mice will be investigated. The third goal of this project is to identify putative cellular proteins which LMP1 interacts with in mediating B cell transformation in EBV infection. Approaches will include affinity purification, lambdagt11 library screening and the yeast two-hybrid system.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.