Epstein-Barr Virus (EBV) is an important human pathogen that is associated with a number of malignancies including Hodgkin’s disease, AIDS related lymphoma, post-transplant lymphoproliferative disease (PTLD), and nasopharyngeal carcinoma. EBV is the only human oncogenic virus for which there is a tissue culture model of infection and transformation. EBV transforms peripheral blood B lymphocytes into lymphoblastoid cell lines (LCLs) that resemble AIDS related lymphomas and PTLD.
LCLs, like most leukemia and lymphomas exhibit high rates of glucose metabolism. Lymphoma proliferation is coupled with a diversion of glucose from ATP synthesis to amino acid, nucleotide and lipid synthesis. In many cancers, tumor suppressors such as PTEN and p53 directly regulate both metabolism and survival. Epstein-Barr Virus transformed lymphomas rarely exhibit any genetic mutations. Rather, EBV transforms lymphocytes by co-opting cellular signaling pathways mimicking B cell receptor (tyrosine kinase pathway), CD40 (NF?B pathway) and Notch signaling pathways to drive proliferation and survival. My ongoing research is focused on the mechanisms by which EBV changes metabolic pathways to support proliferation and survival.
LMP1 mediated NF?B activation is essential for EBV transformation of B lymphocytes into lymphoblastoid cell lines (LCLs). LMP1 functions as a ligand independent, constitutively active CD40-like receptor that activates NF?B. When LMP1 is deleted from the viral genome, the virus is not transforming. LMP1 mutants with diminished NF?B activation are substantially impaired for transforming ability
We have shown that NF?B activity is essential for EBV transformed cell survival and that an important survival function of EBV LMP1 induced NF?B activation is mediated by glucose metabolism. Current studies are focused on biochemical and genetic approaches to dissect this relationship.
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REFERENCES:
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Yuan J, Cahir-McFarland E, Zhao B, Kieff E. Virus and cell RNAs expressed during Epstein-Barr virus replication. J Virol. 2006;80(5):2548-65.
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