Epstein Barr virus (EBV) is associated with 200,000 cases of cancer each year worldwide and is the cause of infectious mononucleosis. The virus is associated with nasopharyngeal carcinoma, gastric carcinoma, Burkitt lymphoma, and Hodgkin disease. The virus causes lymphomas in some persons who have bone marrow or solid organ transplants. Immunodeficient patients with mutations in specific genes, can develop lymphoproliferation associated with EBV or EBV-positive B cell lymphomas. We previously reported several genes (MAGT1, PI3KCD, STXBP1, GATA2, PRF1) associated with severe EBV disease. Boys with mutations in MAGT1 have a disease referred to as XMEN (X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia) due to mutations in MAGT1. While hematopoietic stem cell transplantation (HSCT) has been tried as a curative treatment for XMEN, the results thus far have been disappointing. The three previously reported patients who underwent HSCT all died soon after transplant associated with severe bleeding. This year, we reported our experience with HSCT for XMEN in three boys. Two had successful outcomes with reversal of their disease and control of EBV, but their courses were transiently complicated with bleeding. The third patient had hemorrhagic shock after HSCT and died of multiorgan failure. Therefore, HSCT should be considered for XMEN patients with severe disease. The involvement of mucosal sites with bleeding suggests that XMEN may be associated with a functional disorder of platelets. EBV genome variation is important because some of the diseases associated with EBV have very different incidences in different populations and geographic regions, and differences in the EBV genome might contribute to these diseases. We collaborated with Drs. Paul Farrell and Judith Breuer to study the full-length genomic sequence of EBV in 128 persons, including many persons from our NIH cohort of patients with chronic active EBV disease. Patients with chronic active EBV have high levels of EBV in the blood, indicative of increased virus replication. EBV from saliva of our NIH patients with chronic active EBV infection aligned with the wild-type EBV genome with no evidence of rearrangements, including near the promoter of the gene that activates virus replication. In contrast, a polymorphism in this promoter was frequently found in persons with EBV nasopharyngeal carcinoma. At present the factors that result in EBV reactivation from latency are not well known. In collaboration with Drs. Duane Pierson and Satish Mehta at NASA, we studied the effect of four different types of radiation, gamma rays, protons, carbon ions, and iron ions on the activation of EBV replication genes in latently infected cells in culture. Expression of EBV replication genes was induced and the level of virus in cultured cells was significantly higher for all types of radiation than in corresponding unirradiated cells. This study shows that reactivation of EBV can occur due to the effect of different types of radiation on latently infected cells in the absence of cytokines produced in the immune system. In general, gamma rays were more effective than protons, carbon ions, and iron ions in inducing latent EBV reactivation.
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