Epstein-Barr virus (EBV) is associated with both B cell cancers (Hodgkin lymphoma, Burkitt lymphoma) and epithelial cell cancers (nasopharyngeal carcinoma, gastric carcinoma. Current therapy for several of these diseases is suboptimal. Cellular proteins, referred to as heat shock proteins (HSPs) are molecular chaperones that are important for folding of protein and to reduce protein aggregation during cellular stress. Heat-shock proteins are thought to be particularly important to stabilize viral proteins important for induction of cancer. Inhibitors of one HSP, termed HSP90, have been shown to kill EBV-infected cells by reducing the level of EBV EBNA-1 and/or LMP1. We treated virus-infected cells with a HSP90 inhibitor termed ganetespib, currently being evaluated in multiple clinical trials for cancer and found that the drug killed EBV-positive B and T cells and reduced the level of two EBV proteins, EBNA1 and LMP1, in cells. Treatment of cells with ganetespib also reduced the activation of a cellular protein termed Akt. Ganetespib delayed the onset of EBV-positive lymphomas and prolonged survival in severe immunocompromised mice inoculated with one EBV-transformed cell line, but not another EBV-transformed cell line. The former cell line showed lower levels of EBNA1 after treatment with ganetespib in vitro. Treatment of a patient with T-cell chronic active EBV with ganetespib reduced the percentage of EBV-positive cells in the peripheral blood. These data indicate that HSP90 inhibitors may have a role in the therapy of certain EBV-associated diseases. Some patients infected with EBV develop severe chronic active Epstein-Barr virus (CAEBV) disease with a severe progressive illness lasting 6 months or longer with infiltration of tissues with EBV-positive lymphocytes, markedly elevated levels of EBV DNA in the blood, and no known immunodeficiency such as HIV. These patients usually have fever, splenomegaly, lymphadenopathy, and may have markedly elevated EBV antibody titers to viral capsid antigen. While most experts think that CAEBV disease is due to abnormalities in host cells, it is possible that the disease is due to an abnormal strain of virus. EBV from about 200 Epstein-Barr virus (EBV) isolates, including 12 patients with CAEBV disease at NIH, were sequenced, No clear abnormality was identified in persons with CAEBV disease compared to heathy individuals. A small percentage of healthy white Caucasian people were infected with type 2 EBV, a strain normal only seen in southern Africa and New Guinea. This study is the most comprehensive analysis so far of variation in specific EBV genes. By focusing on variation in EBV genes associated with latent virus infection (LMP, EBNA1), replicative virus infection (BZLF1, gp350), and immune evasion (BART miRNAs), new relationships with the known type 1/type 2 strains were found, and a new classification of some of these genes (EBNA1, BART miRNAs) was developed. We identified a patient with CAEBV who had EBV hepatitis and accumulation of glycogen in hepatocytes. The patient was originally thought to have accumulation of fat (steatosis) based on a sonogram, but a liver biopsy showed glycogen. Therefore, the diagnosis of steatosis cannot be made accurately from a sonogram.
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