Epstein-Barr virus (EBV), a herpesvirus, is a probable human cancer virus as it is oncogenic in sub-human primates, transforms human B lymphocytes in vitro, causes a human lymphoproliferative disorder and the tumor cells in endemic Burkitt's lymphoma and nasopharyngeal carcinoma contain the EBV genome. EBV is also strongly associated with the lymphoproliferative disorders and lymphomas which are major complications of iatrogenic and disease associated immunosuppression; thus virtually all post-transplant B cell proliferative disorders are composed of cells bearing the EBV antigens and many AIDS associated lymphomas contain the EBV genome. The above diseases are invasive, associated with cell and tissue destruction and frequently fatal; all are associated with immunosuppression. Our major long-term objective is the elucidation of the individual and interactive roles played by EBV and cellular genes and gene products, and the contributions of the immune system to the development of EBV-induced human B cell lymphoproliferative disease and lymphomas. We will address these questions in two model systems in immunodeficient mice reconstituted with a functional human immune system; one of these was described recently by Mosier et al. (1988), the other is an as yet unpublished system which we have recently developed in which the contributions of EBV, B cells, and immune surveillance can be independently assessed. In the model described by Mosier et al. (1988), which we have replicated, EBV-containing human B cell lymphomas develop spontaneously 2-4 months after reconstitution of SCID mice with EBV positive but not negative human lymphocytes. In our new model, SCID/hu chimeras develop rapidly fatal human lymphoproliferative disease and tumors 2-4 weeks after injection of EBV; furthermore, the tumor cells grow in vitro and elicit new tumors upon transfer into SCID mice.
Our specific aims are: 1.) to examine the roles of EBV and the target B cell in disease induction with emphasis on the molecular processes involved, and 2.) to examine the contributions of T cell surveillance to the prevention or reversal of disease. We have extensive experience in viral immunobiology and immunology, particularly with regard to EBV, and in the contemporary techniques of molecular genetics. The two model systems described here exhibit many similarities to the lymphoproliferative disorders and lymphomas, which complicate in AIDS and organ transplantation in man. The proposed studies should yield insights into the roles of EBV and the immune system in the pathogenesis of these conditions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA052241-01
Application #
3197047
Study Section
Special Emphasis Panel (SRC (51))
Project Start
1990-05-10
Project End
1995-04-30
Budget Start
1990-05-10
Budget End
1991-04-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Roberts, M L; Cooper, N R (1998) Activation of a ras-MAPK-dependent pathway by Epstein-Barr virus latent membrane protein 1 is essential for cellular transformation. Virology 240:93-9
Chen, W; Huang, S; Cooper, N R (1998) Levels of p53 in Epstein-Barr virus-infected cells determine cell fate: apoptosis, cell cycle arrest at the G1/S boundary without apoptosis, cell cycle arrest at the G2/M boundary without apoptosis, or unrestricted proliferation. Virology 251:217-26
Roberts, M L; Luxembourg, A T; Cooper, N R (1996) Epstein-Barr virus binding to CD21, the virus receptor, activates resting B cells via an intracellular pathway that is linked to B cell infection. J Gen Virol 77 ( Pt 12):3077-85
Chen, W; Cooper, N R (1996) Epstein-Barr virus nuclear antigen 2 and latent membrane protein independently transactivate p53 through induction of NF-kappaB activity. J Virol 70:4849-53
Rochford, R; Hobbs, M V; Garnier, J L et al. (1993) Plasmacytoid differentiation of Epstein-Barr virus-transformed B cells in vivo is associated with reduced expression of viral latent genes. Proc Natl Acad Sci U S A 90:352-6
Garnier, J L; Cannon, M J; Chargui, J et al. (1993) EBV human B-cell lymphomas in Scid mice: description of the model and study of the role of anti-CD40 and anti-CD23 monoclonal antibodies in their development. Transplant Proc 25:1387-8
Garnier, J L; Cooper, N R; Cannon, M J (1993) Low expression of CD20 and CD23 in Epstein-Barr virus-induced B cell tumors in SCID/hu mice. Am J Pathol 142:353-8
Pisa, P; Cannon, M J; Pisa, E K et al. (1992) Epstein-Barr virus induced lymphoproliferative tumors in severe combined immunodeficient mice are oligoclonal. Blood 79:173-9
Moore, M D; Cannon, M J; Sewall, A et al. (1991) Inhibition of Epstein-Barr virus infection in vitro and in vivo by soluble CR2 (CD21) containing two short consensus repeats. J Virol 65:3559-65