Epstein-Barr virus (EBV), a herpesvirus, is a probable human cancer virus as it is oncogenic in sub-human primates, transforms human B lymphocytes in vitro, causes a human lymphoproliferative disorder and the tumor cells in endemic Burkitt's lymphoma and nasopharyngeal carcinoma contain the EBV genome. EBV is also strongly associated with the lymphoproliferative disorders and lymphomas which are major complications of iatrogenic and disease associated immunosuppression; thus virtually all post-transplant B cell proliferative disorders are composed of cells bearing the EBV antigens and many AIDS associated lymphomas contain the EBV genome. The above diseases are invasive, associated with cell and tissue destruction and frequently fatal; all are associated with immunosuppression. Our major long-term objective is the elucidation of the individual and interactive roles played by EBV and cellular genes and gene products, and the contributions of the immune system to the development of EBV-induced human B cell lymphoproliferative disease and lymphomas. We will address these questions in two model systems in immunodeficient mice reconstituted with a functional human immune system; one of these was described recently by Mosier et al. (1988), the other is an as yet unpublished system which we have recently developed in which the contributions of EBV, B cells, and immune surveillance can be independently assessed. In the model described by Mosier et al. (1988), which we have replicated, EBV-containing human B cell lymphomas develop spontaneously 2-4 months after reconstitution of SCID mice with EBV positive but not negative human lymphocytes. In our new model, SCID/hu chimeras develop rapidly fatal human lymphoproliferative disease and tumors 2-4 weeks after injection of EBV; furthermore, the tumor cells grow in vitro and elicit new tumors upon transfer into SCID mice.
Our specific aims are: 1.) to examine the roles of EBV and the target B cell in disease induction with emphasis on the molecular processes involved, and 2.) to examine the contributions of T cell surveillance to the prevention or reversal of disease. We have extensive experience in viral immunobiology and immunology, particularly with regard to EBV, and in the contemporary techniques of molecular genetics. The two model systems described here exhibit many similarities to the lymphoproliferative disorders and lymphomas, which complicate in AIDS and organ transplantation in man. The proposed studies should yield insights into the roles of EBV and the immune system in the pathogenesis of these conditions.
