Leflunomide/teriflunomide inhibit Epstein-Barr virus (EBV)-induced lymphoproliferative disease and lytic viral replication
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Andrea Bilger1, Julie Plowshay2,6, Shidong Ma1,5, Dhananjay Nawandar3,7, Elizabeth A. Barlow1, James C. Romero-Masters4, Jillian A. Bristol1, Zhe Li8, Ming-Han Tsai8, Henri-Jacques Delecluse8 and Shannon C. Kenney1,2
1Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
2Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
3Department Cellular and Molecular Biology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, USA
4Department of Cellular and Molecular Pathology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
5Sanofi Pharmaceuticals, Cambridge, Massachusetts, USA
6Rocky Mountain Infectious Disease Specialists, Aurora, Colorado, USA
7Department of Cancer Biology and Immunology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Cambridge, Massachusetts, USA
8Joint DKFZ Inserm Unit U1074, German Cancer Center (DKFZ), Heidelberg, Germany
Shannon C. Kenney, email: firstname.lastname@example.org
Keywords: therapy, lymphoma, lymphoproliferative disease, humanized mouse model, FDA-approved
Received: March 17, 2017 Accepted: April 27, 2017 Published: May 15, 2017
EBV infection causes mononucleosis and is associated with specific subsets of B cell lymphomas. Immunosuppressed patients such as organ transplant recipients are particularly susceptible to EBV-induced lymphoproliferative disease (LPD), which can be fatal. Leflunomide (a drug used to treat rheumatoid arthritis) and its active metabolite teriflunomide (used to treat multiple sclerosis) inhibit de novo pyrimidine synthesis by targeting the cellular dihydroorotate dehydrogenase, thereby decreasing T cell proliferation. Leflunomide also inhibits the replication of cytomegalovirus and BK virus via both “on target” and “off target” mechanisms and is increasingly used to treat these viruses in organ transplant recipients. However, whether leflunomide/teriflunomide block EBV replication or inhibit EBV-mediated B cell transformation is currently unknown. We show that teriflunomide inhibits cellular proliferation, and promotes apoptosis, in EBV-transformed B cells in vitro at a clinically relevant dose. In addition, teriflunomide prevents the development of EBV-induced lymphomas in both a humanized mouse model and a xenograft model. Furthermore, teriflunomide inhibits lytic EBV infection in vitro both by preventing the initial steps of lytic viral reactivation, and by blocking lytic viral DNA replication. Leflunomide/teriflunomide might therefore be clinically useful for preventing EBV-induced LPD in patients who have high EBV loads yet require continued immunosuppression.
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