Restricted expression of Epstein-Barr virus latent genes in murine B cells derived from embryonic stem cells.
BACKGROUND
Several human malignancies are associated with Epstein-Barr virus (EBV) and more than 95% of the adult human population carries this virus lifelong. EBV efficiently infects human B cells and persists in this cellular compartment latently. EBV-infected B cells become activated and growth transformed, express a characteristic set of viral latent genes, and acquire the status of proliferating lymphoblastoid cell lines in vitro. Because EBV infects only primate cells, it has not been possible to establish a model of infection in immunocompetent rodents. Such a model would be most desirable in order to study EBV's pathogenesis and latency in a suitable and amenable host.


RESULTS
We stably introduced recombinant EBV genomes into mouse embryonic stem cells and induced their differentiation to B cells in vitro to develop the desired model. In vitro differentiated murine B cells maintained the EBV genomes but expression of viral genes was restricted to the latent membrane proteins (LMPs). In contrast to human B cells, EBV's nuclear antigens (EBNAs) were not expressed detectably and growth transformed murine B cells did not arise in vitro. Aberrant splicing and premature termination of EBNA mRNAs most likely prevented the expression of EBNA genes required for B-cell transformation.


CONCLUSIONS
Our findings indicate that fundamental differences in gene regulation between mouse and man might block the route towards a tractable murine model for EBV.
Zychlinska
Magdalena
M
Department of Gene Vectors, Helmholtz Center Munich, German Research Center for Environment and Health, Munich, Germany.
Herrmann
Heidrun
H
Zimber-Strobl
Ursula
U
Hammerschmidt
Wolfgang
W
D000818:Animals; D001402:B-Lymphocytes / Q000821:virology*; D002454:Cell Differentiation; D002460:Cell Line; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic; D053595:Embryonic Stem Cells / Q000166:cytology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000737:chemistry*; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D012333:RNA, Messenger / Q000378:metabolism
D019309:Epstein-Barr Virus Nuclear Antigens; D012333:RNA, Messenger