The long term goal of the proposed research is to identify virologic, immunologic and cellular factors, unique to human mucosa, which contribute to EBV persistence and to mechanisms of pathogenesis. EBV's disease manifestations point to the importance of viral interactions in human mucosa: nasopharyngeal carcinoma and oral hairy leukoplakia (characterized by EBV latency and an aggressively replicative infection, respectively) are epithelial diseases. African Burkitt's lymphoma, with its unusual tissue distribution, is a malignancy of the mucosal-associated lymphoid tissue. Because EBV's two tissue tropisms suggest that the virus may take advantage of the close functional relations between epithelial and lymphoid elements of the common mucosal immune system, we propose the following aims to reach our long term goals: 1) Elucidation of the role of virus-specific IgA in EBV pathogenesis; 2) examination of the role of cellular factors in the regulation of the EBV life cycle in mucosal epithelium; 3) determination of molecular and biological characteristics of EBV variants in the epithelial tissue of oral hairy leukoplakia. Polyclonal human IgA to EBV as well as IgA monoclonal antibodies to the major glycoprotein of EBV (gp350) will be used to analyze """"""""neutralization"""""""" of EBV infectivity for lymphocytes and concurrent IgA-enhanced viral entry into epithelial cells. The possibility of an immune-induced shift in EBV tissue tropisms has tremendous implications for immunization strategy as well as for general concepts of viral pathogenesis. The relation between state of cell differentiation and viral gene expression will be analyzed, first in epithelial tissues of transgenic mice by linking select EBV promoters to beta galactosidase coding sequences; second, in diverse populations of human B lymphocytes, by correlating markers of cell activation/differentiation with virus gene expression. These experiments will elucidate mechanisms of viral persistence and how virus may disseminate after primary infection. Finally, the ability of defective viral DNA to contribute to the high level of viral replication seen in hairy leukoplakia will be examined, first by determination of its structure with cloning and polymerase chain reaction analysis, then by use of novel culture techniques to test its in vitro biologic activity. The existence in nature of a defective virus particle with the ability to enhance, not inhibit, replication of the parent strain suggests mechanisms by which a persistent virus may move from latency to active replication.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA052258-01
Application #
3197066
Study Section
Special Emphasis Panel (SRC (51))
Project Start
1990-05-01
Project End
1995-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Razzouk, B I; Gan, Y J; Mendonca, C et al. (1997) Epstein-Barr virus in pediatric Hodgkin disease: age and histiotype are more predictive than geographic region. Med Pediatr Oncol 28:248-54
Gan, Y J; Chodosh, J; Morgan, A et al. (1997) Epithelial cell polarization is a determinant in the infectious outcome of immunoglobulin A-mediated entry by Epstein-Barr virus. J Virol 71:519-26
Chodosh, J; Gan, Y J; Sixbey, J W (1996) Detection of Epstein-Barr virus genome in ocular tissues. Ophthalmology 103:687-90
Razzouk, B I; Srinivas, S; Sample, C E et al. (1996) Epstein-Barr Virus DNA recombination and loss in sporadic Burkitt's lymphoma. J Infect Dis 173:529-35
Srinivas, S K; Sixbey, J W (1995) Epstein-Barr virus induction of recombinase-activating genes RAG1 and RAG2. J Virol 69:8155-8
Patton, D F; Ribeiro, R C; Jenkins, J J et al. (1994) Thymic carcinoma with a defective Epstein-Barr virus encoding the BZLF1 trans-activator. J Infect Dis 170:7-12
Gan, Y J; Sullivan, J L; Sixbey, J W (1994) Detection of cell-free Epstein-Barr virus DNA in serum during acute infectious mononucleosis. J Infect Dis 170:436-9
Heslop, H E; Li, C; Krance, R A et al. (1994) Epstein-Barr infection after bone marrow transplantation. Blood 83:1706-8
Stewart, J P; Behm, F G; Arrand, J R et al. (1994) Differential expression of viral and human interleukin-10 (IL-10) by primary B cell tumors and B cell lines. Virology 200:724-32
Gan, Y J; Shirley, P; Zeng, Y et al. (1993) Human oropharyngeal lesions with a defective Epstein-Barr virus that disrupts viral latency. J Infect Dis 168:1349-55

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