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 and nasopharyngeal carcinoma. 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 the LMP2A message is the most readily detected EBV-specific message detected in PCR analysis of B lymphocytes from individuals harboring latent EBV infections. Our previous studies have shown that LMP2A is essential for down modulation of cell surface receptor mediated signal transduction in B lymphocytes infected with EBV. By down modulating cell surface signal transduction, LMP2A is important for maintaining EBV latent infection in vitro. Currently, studies designed to elucidate LMPA function in vitro are hampered by the need to use continuous cell lines or EBV transformed lymphoblastoid cell lines (LCLs) which 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 which targets LMP 2A expression to B lymphocytes thereby mimicking in vivo latent infection in humans. 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. 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 preventing the development of AIDS-associated lymphoproliferative disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA073507-10S1
Application #
7282769
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Daschner, Phillip J
Project Start
1997-02-01
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2008-08-31
Support Year
10
Fiscal Year
2006
Total Cost
$99,999
Indirect Cost
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
Rink, Jonathan S; Yang, Shuo; Cen, Osman et al. (2017) Rational Targeting of Cellular Cholesterol in Diffuse Large B-Cell Lymphoma (DLBCL) Enabled by Functional Lipoprotein Nanoparticles: A Therapeutic Strategy Dependent on Cell of Origin. Mol Pharm 14:4042-4051
Fish, Kamonwan; Sora, Richard P; Schaller, Samantha J et al. (2017) EBV latent membrane protein 2A orchestrates p27kip1 degradation via Cks1 to accelerate MYC-driven lymphoma in mice. Blood 130:2516-2526
Yigit, Burcu; Halibozek, Peter J; Chen, Shih-Shih et al. (2016) A combination of an anti-SLAMF6 antibody and ibrutinib efficiently abrogates expansion of chronic lymphocytic leukemia cells. Oncotarget 7:26346-60
Fish, Kamonwan; Chen, Jia; Longnecker, Richard (2014) Epstein-Barr virus latent membrane protein 2A enhances MYC-driven cell cycle progression in a mouse model of B lymphoma. Blood 123:530-40
Brägelmann, J; Dagogo-Jack, I; El Dinali, M et al. (2013) Oral cavity tumors in younger patients show a poor prognosis and do not contain viral RNA. Oral Oncol 49:525-33
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
Chang, Rhoda A; Miller, Stephen D; Longnecker, Richard (2012) Epstein-Barr virus latent membrane protein 2A exacerbates experimental autoimmune encephalomyelitis and enhances antigen presentation function. Sci Rep 2:353
Dargart, Jamie L; Fish, Kamonwan; Gordon, Leo I et al. (2012) Dasatinib therapy results in decreased B cell proliferation, splenomegaly, and tumor growth in a murine model of lymphoma expressing Myc and Epstein-Barr virus LMP2A. Antiviral Res 95:49-56
Shim, Ann Hye-Ryong; Chang, Rhoda Ahn; Chen, Xiaoyan et al. (2012) Multipronged attenuation of macrophage-colony stimulating factor signaling by Epstein-Barr virus BARF1. Proc Natl Acad Sci U S A 109:12962-7
Bieging, Kathryn T; Fish, Kamonwan; Bondada, Subbarao et al. (2011) A shared gene expression signature in mouse models of EBV-associated and non-EBV-associated Burkitt lymphoma. Blood 118:6849-59

Showing the most recent 10 out of 76 publications