Fifty years after discovery of Epstein - Barr virus there is still no effective treatment to interrpt pathogenesis of any EBV infections including those that result in fatal B-cell lymphomas in patients with acquired or inborn immunodeficiency. Rapid development of humanized mice models engrafted with transplanted human hematopoietic stem cells that generate human B, T, and NK cells and a reconstituted human immune system have now provided small animal models suitable for treatment of studies human EBV disease. Infection of humanized NOD/SCID ?C-/- (NSG) mice with EBV produces infection that proceeds from a subclinical phase during which virus is replicated to development of polyclonal EBV B-cell lymphoproliferative disease and ultimately lethal CD20+, EBV EBER-positive, large-cell monoclonal B-cell lymphomas. In a single Aim we will infect with EBV cohorts of NSG mice reconstituted with stem cells from single donors for controlled trials designed to test whether an anti-EBV drug, Maribavir (MBV) alone or together with Rituximab can abort or retard progression from the reversible polyclonal lymphoproliferative phase of disease, when there is cell-to-cell transmission of virus, to irreversible monoclonal lymphoma. Polyclonal and monoclonal phases will be distinguished both by IgH gene rearrangements and EBV genomic terminal probe analyses. Basis for comparisons between treatment and placebo groups will be survival of animals analyzed with Kaplan-Meier survival curves and for statistical significance. These studies will be conducted in blinded fashion and will provide the first prospective, placebo-controlled trials of whether an antiviral drug, either alone or together with the nontoxic anti-tumor agent Rituximab, can affect the course of an EBV malignancy. Results may provide the basis for a nontoxic alternative therapy for these ultimately lethal post-transplant lymphomas. Results may also be of use in patients with AIDS who have rising EBV viral loads that may herald genesis of B-cell lymphomas.

Public Health Relevance

Epstein-Barr virus infection causes B-cell lymphomas in patients who are immunodeficient because they have AIDS or are to receive a transplanted organ. EBV infection of new varieties of humanized mice that have a reconstituted human lymphoid system produces B-cell lymphomas identical to those in humans. These will be the first controlled studies to show whether an anti-EBV drug will prevent or slow genesis of these ultimately fatal lymphomas.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
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Dempsey, Walla L
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Whitehurst, Christopher B; Li, Guangming; Montgomery, Stephanie A et al. (2015) Knockout of Epstein-Barr virus BPLF1 retards B-cell transformation and lymphoma formation in humanized mice. MBio 6:e01574-15
Kumar, Ravindra; Whitehurst, Christopher B; Pagano, Joseph S (2014) The Rad6/18 ubiquitin complex interacts with the Epstein-Barr virus deubiquitinating enzyme, BPLF1, and contributes to virus infectivity. J Virol 88:6411-22
Whitehurst, Christopher B; Sanders, Marcia K; Law, Mankit et al. (2013) Maribavir inhibits Epstein-Barr virus transcription through the EBV protein kinase. J Virol 87:5311-5