Pathogenesis and Chemotherapy of Human Virus Infections

National Institute Of Allergy And Infectious Diseases

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Abstract

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. Patients with X-linked MAGT1 deficiency have increased susceptibility to severe Epstein-Barr virus (EBV) disease and may develop EBV lymphomas. The original studies of XMEN patients focused on impaired magnesium regulation, leading to decreased EBV-cytotoxicity and the loss of surface expression of a lymphcoyte activating receptor "natural killer group 2D" (NKG2D) on CD8+ T cells and NK cells. In vitro studies showed that supraphysiological supplementation of magnesium rescued the impaired EBV-cytotoxicity and upregulated expression of NKG2D on the T cells. Observational studies in 2 patients suggested oral magnesium supplementation could decrease EBV viremia. In 2022 we completed a randomized, double-blind, placebo-controlled, crossover study in 2 parts. In part 1, patients received either oral magnesium L-threonate (MLT) or placebo for 12 weeks followed by 12 weeks of the other treatment. Part 2 began with 3 days of high-dose intravenous (IV) magnesium sulfate (MgSO4) followed by open-label MLT for 24 weeks. One EBV-infected and 3 EBV-naive patients completed part 1. One EBV-naive patient was removed from part 2 of the study due to asymptomatic elevation of liver enzymes during IV MgSO4. No change in EBV viremia or NKG2D expression on T or NK cells was observed. In vitro magnesium supplementation experiments in cells from 14 XMEN patients failed to significantly increase NKG2D expression and the clinical trial was stopped. Although small, this study indicates magnesium supplementation is unlikely to be an effective therapeutic option in XMEN disease. West Nile virus is a flavivirus that often causes fever in infected humans, but in some persons particularly the elderly and persons with impaired cellular immunity, the virus can result in severe encephalitis and death. In 2022 we examined the regulation of the immune and nervous system in a nonhuman primate model of West Nile virus neurological disease. We found that West Nile virus infection disrupted transcriptional regulation of both the immune and neural system. This resulted in activation of non-neuronal responses to West Nile virus infection and disruption of the structural integrity and function of virus infected neurons. West Nile virus infection disrupted the transcriptional regulation of organization and function of synapses resulting destruction of synapses with severe impairment of neurologic impairment.