In healthy seropositive persons (and in Burkitt s lymphoma) EBV infection of circulating lymphocytes is in a highly restricted form called type I latency in which only the BamHI Q promoter (Qp) is active, and the EB nuclear antigen 1 (EBNA-1) is expressed. During studies of Qp, which have the long-term objective of understanding how latency is established and maintained and how episomal replication is synchronized with cell cycle, the applicant has isolated a new gene in the family of interferon regulatory factors (IRFs), which are transcriptional factors that bind to the conserved interferon-stimulated responsive element (ISRE) and serve as transactivators or repressors. The protein products of the new gene, IRF-4A, -4B, -4C, bind to an ISRE site in Qp, apparently the first functional ISRE characterized in a viral promoter. Moreover, interferon alpha (IFN-a) appears to activate Qp during primary infection. These findings have opened a new field for exploration, namely, how IRFs and IFN may affect EBV infection, particularly latency. A second mechanism governing Qp centers on regulation of transcription of EBNA1 mRNA by the cell cycle, reciprocally mediated by E2F and EBNA-1. Experiments will address: 1) further characterization of IRF-4 and involvement of other IRF members in Qp regulation; 2) the function of IFN-a in the activation of Qp and its possible biological consequence; 3) timing of expression of EBNA-1 mRNA and protein during cell cycle and mechanism of cell-cycle activation of Qp. Results from the proposed experiments should offer new insights into how these cellular and viral factors unite to regulate transcription of the EBNA-1 gene from Qp, which is central to understanding EBV-host interaction and the viral latency and transformation processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042371-05
Application #
6475496
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Beisel, Christopher E
Project Start
1997-12-01
Project End
2003-11-30
Budget Start
2001-12-01
Budget End
2003-11-30
Support Year
5
Fiscal Year
2002
Total Cost
$246,628
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599