Our group studies the Epstein Barr Herpesvirus, which has long term latency in human B lymphocytes and causes Infectious Mononucleosis, Lymphoproliferative Diseases in immune compromised and HIV infected people, Burkitt's Lymphoma, ~50% of Hodgkin's Disease, anaplastic Nasopharyngeal Carcinoma, and antral gastric carcinomas. Oncogenic human viruses offer exceptional opportunities to investigate cell pathways relevant to cancer, cell proliferation, and cell survival, using biochemical tools and genetics based in the causative virus. The EBV genome has 89 genes; large for a virus but at least 400 fold less complex than the diploid human genome. Nevertheless, EBV effects nearly immediate changes in infected B-cell signal transduction, transcription, growth, and survival. Genetic and biochemical studies of virus infection contribute new knowledge to virology, but also to cell biochemistry, biology, gene regulation, genetics and immunology. Our experiments begin with studies of the fundamental mechanisms by which Epstein-Barr Virus uniquely and efficiently causes the uncontrolled proliferation and survival of normal human B lymphocytes as lymphoblastoid cell lines. EBV has five nuclear protein genes (EBNA2, EBNALP, EBNA3A, EBNA3C, and EBNA1) and 1 integral membrane protein (LMP1), which are essential for efficient B cell proliferation and survival, as well as multiple micro RNA genes. EBNA1 is essential for EBV episome persistence, where as EBNA2 and EBNALP initially coordinately activate virus and cell gene transcription. EBNA2 evolved to enter 5-thousand, pre-existing, enhancer sites, including sites 400kb upstream of myc, to cause myc driven cell proliferation. In collaboration, EBNALP mediates EBNA2 enhancer looping to promoter sites and removes repressors from thousands of promoters, including the myc promoter. EBNA3A and EBNA3C foster these affects, by suppressing CDKN2A p14 and p16 transcription, preventing myc-induced p14 and p16 suppression of cell proliferation. EBNA2, EBNALP, EBNA3A, and EBNA3C usurp control of Notch regulated cell promoters, including the c-myc promoter, providing evidence for the central importance of this pathway for lymphocyte proliferation and survival in B-cell and T-cell lymphoma and leukemia. EBV encoded LMP1 constitutively activates CD40 signaling pathways and studies of LMP1 inform signaling, metabolic, and cell survival effects downstream of TNF receptors. We are currently investigating the genetics, biochemistry, and systems cell biology of the molecular and sub-molecular processes through which these viral proteins change lymphocyte signal transduction, transcription, growth, metabolism, and survival, so as to better identify specific chemicals inhibitors of these pathways.

Ongoing projects for fellows and students include elucidation of: (i) Pre-existing cell transcription factor pathways usurped by EBNA2, EBNALP, EBNA3A, and EBNA3C or by Notch to up-regulate and remodel transcriptional regulatory sites to cause human leukemias and lymphomas. (ii) Systems wide cooperative effects of activation of thousands of genes to coordinately mediate growth and survival downstream of EBNA2, EBNALP, LMP1 or CD40, and LMP2 co-stimulated cell survival and growth. (iii) Biochemical processes through which EBV permits episome replication and persistence. (iv) Genetic and reverse genetic analyses of the effects of EBV replication, packaging and envelopment on the cell proteome and transcriptome. and (v) Role of EBV encoded micro RNAs in latency and replication.