EBV Genome Organization in Lymphoblastoid Cell Lines Established Following Enhancement With Aflatoxin B1 and Relevance to Nasopharyngeal Carcinoma
The mechanisms underlying interactions between viruses and carcinogens are only beginning to be understood. Peripheral blood lymphocytes (PBLs) separated from patients with acquired immunodeficiency syndrome (AIDS) are a relevant model to study chemical carcinogen-EBV synergism, due to the high degree of EBV reactivation and potential for EBV-associated malignant lymphomas in patients with AIDS. To better understand chemical carcinogen-EBV synergism at a molecular level, we examined the organization of the terminal region of EBV genome carried by LCLs established from patients with AIDS. For this study we chose LCLs established from PBLs treated with aflatoxin B1 (AFB1), a mycotoxin and known carcinogen. From an analysis of the EcoR1 Dhet terminal region, we found the majority of the LCLs established spontaneously to be clonal in origin, but individual lineages established from the same patient often carried EBV episomal circular forms of the genome with varying numbers of fused 500-base pair terminal repeats. Linear forms of the EBV genome with varying numbers of fused 3’ and 5’ 500-base pair terminal repeats were only detected in spontaneously derived LCLs which were established from carcinogen-treated PBLs. The presence of linear EBV DNA correlated with the presence of extracellular transforming virus. LCLs established from PBLs separated from patients with AIDS following addition of exogenous EBV (B95.8 or FF41–1) most often carried episomal circular forms of EBV genome with a terminal region characteristic of the infecting viral strain. LCLs derived from EBV-infected PBLs treated with AFB1 often carried variation of the parent episomal circular form differing in terminal region varying by number of fused terminal repeats. In addition, various forms of linear EBV DNA varying by the number of fused 3’ terminal repeats could be detected in these LCLs. These results show that the chemical carcinogen AFB1 directly interact with EBV and drive EBV-infected lymphocytes toward a semi-permissive infection. Furthermore, the permissive state of an LCL correlates with changes in the organization of the terminal region of the EBV genome and provides a model to explore how chemical carcinogens enhance EBV-induced transformation and EBV replication, and induce malignant conversion of EBV-carrying LCLs.
KeywordsTerminal Region Terminal Repeat Chemical Carcinogen Spontaneous Transformation Malignant Conversion
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