The biological properties of different Epstein-Barr virus strains explain their association with various types of cancers

// Ming-Han Tsai 1, 2 , Xiaochen Lin 1, 2, * , Anatoliy Shumilov 1, 2, * , Katharina Bernhardt 1, 2 , Regina Feederle 1, 2, 3 , Remy Poirey 1, 2 , Annette Kopp-Schneider 4 , Bruno Pereira 5 , Raquel Almeida 5 , Henri-Jacques Delecluse 1, 2 1 German Cancer Research Centre (DKFZ), Unit F100, 69120 Heidelberg, Germany 2 Inserm unit U1074, DKFZ, 69120 Heidelberg, Germany 3 Institute for Diabetes and Obesitas, Monoclonal Antibody Core Facility, German Research Center for Environmental Health, Helmholtz Zentrum Munchen, 81377 Munich, Germany 4 German Cancer Research Centre (DKFZ), Unit C060, 69120 Heidelberg, Germany 5 Differentiation and Cancer Group, IPATIMUP, Rua Dr Roberto Frias s/n, 4200 - 465 Porto, Portugal * These authors have contributed equally to the study Correspondence to: Henri-Jacques Delecluse, email: h.delecluse@dkfz.de Keywords: human tumor viruses, Epstein-Barr virus strains, viral infection and transformation, host-virus interactions, carcinoma and lymphoma Received: October 12, 2016     Accepted: December 15, 2016     Published: December 30, 2016 ABSTRACT The Epstein-Barr virus (EBV) is etiologically associated with the development of multiple types of tumors, but it is unclear whether this diversity is due to infection with different EBV strains. We report a comparative characterization of SNU719, GP202, and YCCEL1, three EBV strains that were isolated from gastric carcinomas, M81, a virus isolated in a nasopharyngeal carcinoma and several well-characterized laboratory type A strains. We found that B95-8, Akata and GP202 induced cell growth more efficiently than YCCEL1, SNU719 and M81 and this correlated positively with the expression levels of the viral BHRF1 miRNAs. In infected B cells, all strains except Akata and B95-8 induced lytic replication, a risk factor for carcinoma development, although less efficiently than M81. The panel of viruses induced tumors in immunocompromised mice with variable speed and efficacy that did not strictly mirror their in vitro characteristics, suggesting that additional parameters play an important role. We found that YCCEL1 and M81 infected primary epithelial cells, gastric carcinoma cells and gastric spheroids more efficiently than Akata or B95-8. Reciprocally, Akata and B95-8 had a stronger tropism for B cells than YCCEL1 or M81. These data suggest that different EBV strains will induce the development of lymphoid tumors with variable efficacy in immunocompromised patients and that there is a parallel between the cell tropism of the viral strains and the lineage of the tumors they induce. Thus, EBV strains can be endowed with properties that will influence their transforming abilities and the type of tumor they induce.