PATHOGENESIS OF EBV ASSOCIATED AIDS LYMPHOMAS

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Individuals with Acquired Immune Deficiency Syndrome (AIDS) are at increased risk for the development of B cell lymphomas that are positive for Epstein-Barr virus (EBV) infection. A direct role for EBV in the etiology of these lymphomas is suspected, but the virus-host interactions that contribute to lymphomagenesis remain unclear. The long-term goals of our studies are to determine how EBV regulates the cellular processes of growth, differentiation, and death in B cells such that, in the context of profound host immunodeficiency, a malignant state is achieved. We propose to examine these processes in cells derived from four sources: I) EBV-infected lymphoblastoid cell lines (LCL); ii) B cell lines transfected with EBV genes; iii) B cell lymphomas derived from SCID mice reconstituted with EBV-infected B cells (hu-PBL-SCID mice); iv) AIDS-related lymphomas (ARL). To decipher the role of cytokine-mediated autocrine growth in lymphomagenesis, hu-PBL-SCID lymphomas, ARL, and LCL will be analyzed for the expression of growth-regulating cytokines and cytokine receptors. We will then use neutralizing anti-cytokine mAbs to determine whether the growth of these three cell types in vitro or the development of lymphomas in SCID mice is dependent upon cytokine expression. Also, we will use EBV gene-transfected cell lines to examine the role of EBV proteins in the regulation of cytokine and cytokine receptor expression. To assess whether EBV infection alters distinct apoptotic pathways in B cells, hu-PBL-SCID lymphomas, ARL, and LCL will be analyzed in vitro for their sensitivity to various inducers of cell death. In addition, we will evaluate the three cell types for the relative levels of expression of pro-and anti-death genes, and we will use EBV gene-transfectants to uncover virus-host interactions leading to altered cell death programs. To evaluate the role of differentiative processes in lymphomagenesis, ARL will be assessed for immunophenotypic heterogeneity and for patterns of viral gene expression. To model differentiative change in the ARL, we will isolate lymphoblastoid and plasmacytoid cell subsets from hu-PBL- SCID lymphomas and test for subset-specific differences in patterns of cell growth, cell death, and expression of relevant host and viral genes. Lastly, cytokines will be screened in vitro for their capacity to induce differentiation of the lymphoblastoid subset and LCL, and to alter their patterns of EBV gene expression. Results from these studies should contribute to the design of therapies to block growth or to induce death or terminal differentiation of ARL in patients.