? DESCRIPTION (provided by applicant): Epstein Barr virus (EBV) has a well-defined association with human T-cell lymphomas and T-cell lymphoproliferative disorders (LPD). T-cell LPD, including chronic active EBV, occurs primarily in immunocompetent children and young adults. This disease has an aggressive clinical course and can progress to a monoclonal T cell lymphoma. In either T cell LPD or lymphoma, EBV can be detected in CD8+ T-cells and CD4+ T-cells with the virus predominantly existing as a latent infection. Despite the consistent detection of EBV in T cells in patients with these diseases, the role that EBV plays in the etiology remains unknown. A major roadblock in our understanding of the etiology of EBV-associated T cell diseases is the lack of suitable model systems to study EBV infection of T cells. Until recently, the major strain of EBV, EBV- Type 1 (-1) was the primary model to study EBV infection and it does not readily infect primary T cells. However, we have shown that EBV-2 readily infects CD8+ T-cells in vitro. This event leads to cell proliferation and activation, and also alteration of the cytokine profile. Moreover, EBV-2 infected T cell cultures survive for 10 weeks in the absence of exogenous IL-2 suggesting this virus induces pro-survival cell programs. The EBV latent genes, LMP-1, EBNA-1, and EBNA-2, were expressed and indicative of the growth latency program. Infection of T cells with EBV-2 provides us with a new tool to dissect how EBV contributes to EBV-associated T cell lymphomas and LPD. An essential next step is to develop an in vivo model. In this R21, we propose to use a humanized mouse model to understand EBV driven T cell lymphomagenesis. Specifically, we will use the BALB/c-Rag2nullIL2r?null (BRG) hematopoietic humanized model engrafted with CD34+ hematopoietic stem cells (hu-mice) that recapitulates many aspects of human lymphocyte development and function. We will test the hypothesis that infection of hu-mice with EBV-2 will lead to infection o CD8+ T cells, expansion of the infected T cells and aberrant cytokine expression. To test our hypothesis, we will determine the cellular tropism of EBV-2 in hu-mice, determine the pattern of viral gene expression in EBV-2 infected cells in hu-mice and evaluate how EBV-2 infection alters the development of CD8+ T cells in hu-mice. Completion of this research will enhance our understanding of the biology of EBV-2 and lead to development of a model system in which the consequence of EBV infection on T cells can be elucidated.

R21AI122670

2016-01-01

2018-06-30