This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Epstein-Barr virus infection is closely associated with the development of several human malignancies, including the endemic form of Burkitt?s lymphoma and nasopharyngeal carcinoma. The major goal of this research is to understand the regulation of EBF gene expression during restricted viral latency (group 1 or group 2 latency), observed in the EBV-associated tumors that arise in immunocompetent individuals. Specifically, of the six Epstein-Barr nuclear antigens (EBNAs) expressed during the growth transforming form of EBV latency (group 3 latency), only EBNA1 is expressed during restricted viral latency. EBNA1 is essential for maintenance of the viral episome, and has recently been shown to be refractile to presentation by MHC class I. Thus, expression of EBNA1 does not lead to recognition of tumor cells by the host immune response. Recent characterization of the long term reservoir in healthy seropositive individuals indicates that EBV is present in a population of memory B cells in which there is minimal viral gene expression, suggesting that a restricted form of viral latency may also be involved in persistence in vivo. We have identified a distinct viral promoter, Qp, involved in driving exclusing expression of the EBNA1 gene during restricted viral latency; characterized methylation of the viral genome and observed a tight correlation between methylation of the EBNA gene promoters Cp and Wp (active during group 3 latency) and establishment of restricted viral latency; determined that the region around Qp remains hypomethylaed during either restricted viral latency or group 3 latency; and mapped critical cis-elements involved in regulating Qp activity, including identification and characterization of an IRF1/IRF2 site adjacent to the site of transcription initiation.
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