Epstein-Barr virus (EBV) causes infectious mononucleosis in adolescents and malignant B lymphocyte proliferation in AIDS patients and patients undergoing immune suppression for organ transplantation. EBV is etiologically associated with African Burkitt's lymphoma (BL), Hodgkin's lymphoma (HL) and nasopharyngeal carcinoma (NPC). In vitro, EBV transformed, latently infected B lymphocytes contain EBV episomes and nine virus encoded proteins. Six are nuclear proteins (EBNAs) and three are the integral membrane proteins, LMP1, LMP2A, and LMP2B. These nine proteins are presumed to mediate latent virus infection or B lymphocyte proliferation and thus are under intense investigation. Besides EBNA1, which is required for episome maintenance, LMP1, LMP2A, and LMP2B are the latently expressed proteins consistently detected in EBV related malignancies and EBV-associated diseases in HIV/AIDS patients. Currently, studies designed to elucidate LMP2A function in vitro are hampered by the need to use continuous cell lines or EBV transformed lymphoblastoid cell lines (LCLs) that do not reflect the unactivated B lymphocyte in which EBV is latent in the human host. To begin to understand the function of LMP2A in latent infection, we have developed a murine transgenic model system that targets LMP2A expression to B lymphocytes. The model has proved useful in characterizing the alteration of normal B cell function by LMP2A and has proved invaluable in investigating the requirements for LMP2A function in latent infection. This model has also provided clues in regard to how LMP2A may contribute to EBV-associated disease in HIV/AIDS patients. In the current proposal, we will continue our analysis of LMP2A function in our transgenic mice using both in vitro and in vivo techniques. An understanding of LMP2A function may provide insight for the development of novel therapeutics for the treatment or eradication of EBV latent infections in the human host, thereby lessening EBV-associated lymphoproliferative disease and other EBV- related pathologies in HIV/AIDS patients and in patients with immune dysfunction such as those undergoing immune suppression for organ transplantation.

Public Health Relevance

Our specific aims are to identify cellular and viral factors that are important for Epstein-Barr virus (EBV) latent infections and EBV-associated hematological cancers and proliferative disorders that occur in the human host and those in particular that occur in HIV/AIDS patients. An understanding of how EBV contributes to EBV lymphoproliferative disease and other EBV-related pathologies in HIV/AIDS patients may provide insight for the development of novel therapeutics for the treatment or eradication of EBV-associated disease in HIV/AIDS patients, the ultimate goal of our studies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073507-15
Application #
8220766
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Daschner, Phillip J
Project Start
1997-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
15
Fiscal Year
2012
Total Cost
$366,175
Indirect Cost
$123,675
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Vrazo, Alexandra C; Chauchard, Maria; Raab-Traub, Nancy et al. (2012) Epstein-Barr virus LMP2A reduces hyperactivation induced by LMP1 to restore normal B cell phenotype in transgenic mice. PLoS Pathog 8:e1002662
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Cen, Osman; Longnecker, Richard (2011) Rapamycin reverses splenomegaly and inhibits tumor development in a transgenic model of Epstein-Barr virus-related Burkitt's lymphoma. Mol Cancer Ther 10:679-86
Bieging, Kathryn T; Swanson-Mungerson, Michelle; Amick, Alexandra C et al. (2010) Epstein-Barr virus in Burkitt's lymphoma: a role for latent membrane protein 2A. Cell Cycle 9:901-8
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Bieging, Kathryn T; Amick, Alexandra C; Longnecker, Richard (2009) Epstein-Barr virus LMP2A bypasses p53 inactivation in a MYC model of lymphomagenesis. Proc Natl Acad Sci U S A 106:17945-50
Bultema, R; Longnecker, R; Swanson-Mungerson, M (2009) Epstein-Barr virus LMP2A accelerates MYC-induced lymphomagenesis. Oncogene 28:1471-6
Ikeda, Masato; Longnecker, Richard (2009) The c-Cbl proto-oncoprotein downregulates EBV LMP2A signaling. Virology 385:183-91

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