The first animal model for "Hit and Run" theory of oncogenesis by EBV related virus

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Epstein-Barr virus associated hemophagocytic syndrome (EBV-AHS) is often associated with fatal infectious mononucleosis or T -cell lymphoproliferative diseases (LPD). To elucidate the pathogenesis of fatal Herpesvirus papio (HVP)-infected LPD and subsequently developed HVP-negative lymphomas observed in HVP-induced rabbit hemophagocytic syndrome, we analyzed sequential examination by ultrasonography (US), CT,CBC, antibody titers, viral quantification, liver biopsy of HVP-induced rabbit LPD and lymphoma development. All of the nine Japanese White rabbits inoculated intravenously with HVP died of fatal LPD or lymphomas. LPD was often accompanied by hemophagocytic syndrome (HPS). Sequential laboratory examinations revealed the increase or decrease of anti-EBV-VCA-IgG titers and viral roads. US or CT examination showed the continuously enlarged splenomegaly. Liver biopsy revealed the transient HVP-EBER-1-positive atypical lymphocyte infiltration. Autopsy examination reconfirmed the development of HVP-EBER-1-negative lymphomas in 2 infected rabbits with long survival and HVP-infected LPD in all cases. Hemophagocytic histiocytosis was observed in the lymph nodes, spleen, bone marrow, or thymus. HVP-DNA was detected in the tissues and peripheral blood from the infected rabbits by PCR or Southern blot analysis. These data suggest that HVP-negative lymphomas developed among HVP-positive LPD may be the good model for "hit and run" oncogenesis theory by herpesvirus.