ETIOLOGY OF AIDS-RELATED EBV-ASSOCIATED T CELL LYMPHOMA

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Improved survival of patients with acquired immunodeficiency syndrome (AIDS), due to combinational antiretroviral therapy and prophylaxis for opportunistic infections, is paralleled by an increasing number of AIDS- non-Hodgkin's lymphomas (AIDS-NHLs). Among AIDS-NHLs, Epstein-Barr virus (EBV)-associated T cell non-Hodgkin's lymphomas (T-NHLs) are recognized as a new distinct clinicopathological entity. EBV-associated T-NHL develop primarily in patients with AIDS. In contrast to EBV-associated B-NHL, little is known about the etiology, biology or therapy of EBV-associated T-NHL. We had previously demonstrated the ability of EBV to infect primary CD4+ and CD8+ T cells, and identified a partial EBV transcriptional program in T cells that included immediate-early transcriptional transactivators BZLF1 and BRLF1. More recently we have observed long-term proliferation of EBV-infected CD4+ lymphocytes leading to CD4+ T lymphoblastoid cell lines (LCLs) carrying latent EBV and encoding latent mRNA transcripts. In addition, we have engineered T cell lines that express B cell-derived CR2 (EBV receptor) that can be infected by EBV at a high efficiency. Using these three models, EBV infection of primary T cells, EBV-carrying T LCLs and CR2-expressing T cell lines, we propose to analyze EBV infection of T cells at the cellular and molecular level. Specifically we propose to study the fate of EBV virion DNA, viral transcriptional program and the effects of EBV - infection on T cell physiology, including cytokine profiles, NF-kappaB activation and ability to support HIV-1 replication. The proposed system of reproducing persistent EBV infection in T cells leading to EBV-carrying LCLs should be a good model for investigating the pathogenic role of EBV in T cell lymphomas and possible role in disease progression. The proposed studies will shed light on events that occur between EBV infection of T cells and the development of T cell lymphoma. Specifically, identification of the EBV transcriptional program in primary T cells and EBV-carrying T LCLs should lead to better understanding and treatment strategies for EBV- associated T-NHL, which is presently associated with poor prognosis.