Epstein Barr virus (EBV) is a cause of infectious mononucleosis and is associated with a number of cancers including Burkitt lymphoma and lymphoma in transplant recipients. Chronic active EBV (CAEBV) disease is an often fatal disease in which patients have markedly elevated levels of antibody to EBV or EBV DNA in the blood, and infiltration of tissues with EBV-infected lymphocytes. Last year, in collaboration with Michael Lenardo in the Laboratory of Immunology, NIAID, we found that one of our patients with CAEBV disease who died of an EBV-positive lymphoma had a mutation in a gene important for magnesium transport (MagT1). The patient's T cells had reduced baseline levels of free magnesium and defective magnesium and calcium influx when they were stimulated with a potent T cell stimulus (an antibody to the T cell receptor). The patient's peripheral blood cells were impaired for activating several proteins in signaling pathways (NF-Kappa B, NFAT, PLC-gamma-1, PKC-theta), Since T lymphocytes are important for killing EBV-infected cells, the impaired activation of T lymphocytes in the patient associated with the mutation in MagT1 was likely responsible for his severe CAEBV disease. This year in collaboration with Dr. Michael Lenardo, we showed that patients with mutations in MagT1 have reduced expression of a protein (NKG2D) present on natural killer (NK) and cytotoxic (CD8) T cells that is important for activation of the cells and their ability to kill target cells. Cells from patients that have mutations in MagT1 are impaired for killing Epstein-Barr virus-infected cells and these patients have a high rate of Epstein-Barr virus B cell lymphomas. Addition of magnesium to the patient's cells in culture increased the level of the NKG2D protein on the surface of the cells and improved killing of Epstein-Barr virus-infected cells. Intravenous or oral magnesium supplements given to patients with mutations in MagT1 increased expression of the NKG2D on the surface of their cells, and reduced the number of copies of EBV DNA in their cells. This year in another collaboration with Dr. Lenardo we identified a mutation in PI3K p110 delta in one of our patients that resulted in impaired control of EBV. The mutation identified was a gain-of-function mutation that increased the kinase function of the PI3K p110 delta protein. In addition to severe EBV infections, our patient and others at NIH with the mutation had severe CMV infections, bacterial infections of the sinus and lungs, enlarged lymph nodes, and nodular hyperplasia of lymphoid tissues in the airways and gastrointestinal tract. Some of the patients developed EBV lymphomas. The patients had reduced numbers of naive T cells, an increased number of senescent effector T cells, and hyperactivation of the mTOR kinase. Treatment of one patient with an mTOR inhibitor, rapamycin, reduced the T cell lymphoproliferation and increased the number of nave T cells.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Niaid Extramural Activities
Zip Code
Bollard, Catherine M; Cohen, Jeffrey I (2018) How I treat T-cell chronic active Epstein-Barr virus disease. Blood 131:2899-2905
Cohen, Jeffrey I (2018) Vaccine Development for Epstein-Barr Virus. Adv Exp Med Biol 1045:477-493
Levoska, Melissa A; Cohen, Jeffrey I; Manoli, Irini et al. (2018) Recurrent scarring papulovesicular lesions on sun-exposed skin in a 22-year-old man. J Am Acad Dermatol 78:637-642
Cohen, Jeffrey I (2018) Herpesviruses in the Activated Phosphatidylinositol-3-Kinase-? Syndrome. Front Immunol 9:237
Coghill, Anna E; Bu, Wei; Hsu, Wan-Lun et al. (2018) Evaluation of Total and IgA-Specific Antibody Targeting Epstein-Barr Virus Glycoprotein 350 and Nasopharyngeal Carcinoma Risk. J Infect Dis 218:886-891
Kimura, Hiroshi; Cohen, Jeffrey I (2017) Chronic Active Epstein-Barr Virus Disease. Front Immunol 8:1867
Correia, Samantha; Palser, Anne; Elgueta Karstegl, Claudio et al. (2017) Natural Variation of Epstein-Barr Virus Genes, Proteins, and Primary MicroRNA. J Virol 91:
Burbelo, Peter D; Gunti, Sreenivasulu; Keller, Jason M et al. (2017) Ultrarapid Measurement of Diagnostic Antibodies by Magnetic Capture of Immune Complexes. Sci Rep 7:3818
Cohen, Jeffrey I (2017) GATA2 Deficiency and Epstein-Barr Virus Disease. Front Immunol 8:1869
Shatzer, Amber; Ali, Mir A; Chavez, Mayra et al. (2017) Ganetespib, an HSP90 inhibitor, kills Epstein-Barr virus (EBV)-infected B and T cells and reduces the percentage of EBV-infected cells in the blood. Leuk Lymphoma 58:923-931

Showing the most recent 10 out of 39 publications