Epstein-Barr virus (EBV) infects most humans and causes infectious mononucleosis. In some immune suppressed humans, such organ transplant recipients, children with generic susceptibility or AIDS patients, EBV causes an acute malignant lymphoproliferative disease. EBV can predispose an infected cell to evolve into a Burkitt lymphoma or a nasopharyngeal carcinoma. EBV efficiently transforms normal B lymphocytes so they can proliferate indefinitely, in vitro, in SCID mice or in tarmarins. The goal of this research program is to delineate the biochemical processes by which EBV infects and alters human B lymphocyte growth. In transformed human B lymphocytes EBV expresses six nuclear proteins (EBNA-1, -2,-3A, -3B, -3C and-LP), two integral membrane proteins (LMP-1 and LMP-2) and two small RNAs (EBERS). The genes and gen products are characterized. Relevant biochemical effects of these genes in B lymphocytes are also known. Initial data from recombinant EBV molecular genetic analyses indicates that EBNA-2, -LP, -3A, -3C and LMP-1 are critical for lymphocyte growth transformation; and that EBNA-3B LMP-2 and the EBERs are not. (EBNA-1 has not been evaluated. The objectives of this proposal are (i) to continue the delineation of the biochemical pathways by which these genes effect lymphocyte growth. (ii) to exploit recently developed recombinant EBV molecular genetics to define domains of these genes of the encoded proteins which are critical for EBV effects on lymphocyte growth. (iii) to couple the genetic and biochemical analyses so as more rapidly delineate essential interactions. (iv) to characterize B lymphocyte genes whose expression is altered by EBV infection and to place these genes in the pathways of EBV and antigen effects. Collaborative interactions to further characterize relevant aspects of human EBV infection and of the immune response will continue. These experiments may identify pharmacologic targets for inhibiting EBV infection and contribute to the development of EBV vaccines and vectors. Since the effects of EBV on B lymphocytes closely parallel those of antigen stimulation, these studies are expected to increasingly intersect with and contribute to pathways of antigen driven B lymphocyte proliferation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA047006-14
Application #
6172260
Study Section
Special Emphasis Panel (SRC (88))
Program Officer
Daschner, Phillip J
Project Start
1987-06-01
Project End
2002-03-31
Budget Start
2000-06-07
Budget End
2002-03-31
Support Year
14
Fiscal Year
2000
Total Cost
$1,572,115
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Wang, Chong; Zhou, Hufeng; Xue, Yong et al. (2018) Epstein-Barr Virus Nuclear Antigen Leader Protein Coactivates EP300. J Virol 92:
Ohashi, Makoto; Holthaus, Amy M; Calderwood, Michael A et al. (2015) The EBNA3 family of Epstein-Barr virus nuclear proteins associates with the USP46/USP12 deubiquitination complexes to regulate lymphoblastoid cell line growth. PLoS Pathog 11:e1004822
Zhao, Bo; Barrera, Luis A; Ersing, Ina et al. (2014) The NF-?B genomic landscape in lymphoblastoid B cells. Cell Rep 8:1595-606
Heilmann, Andreas M F; Calderwood, Michael A; Portal, Daniel et al. (2012) Genome-wide analysis of Epstein-Barr virus rta DNA binding. J Virol 86:5151-64
Xing, Li; Kieff, Elliott (2011) cis-Acting effects on RNA processing and Drosha cleavage prevent Epstein-Barr virus latency III BHRF1 expression. J Virol 85:8929-39
Calderwood, Michael A; Lee, Sungwook; Holthaus, Amy M et al. (2011) Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. Virology 414:19-25
Maruo, Seiji; Zhao, Bo; Johannsen, Eric et al. (2011) Epstein-Barr virus nuclear antigens 3C and 3A maintain lymphoblastoid cell growth by repressing p16INK4A and p14ARF expression. Proc Natl Acad Sci U S A 108:1919-24
Lee, Sungwook; Sakakibara, Shuhei; Maruo, Seiji et al. (2009) Epstein-Barr virus nuclear protein 3C domains necessary for lymphoblastoid cell growth: interaction with RBP-Jkappa regulates TCL1. J Virol 83:12368-77
Maruo, Seiji; Wu, Yi; Ito, Taku et al. (2009) Epstein-Barr virus nuclear protein EBNA3C residues critical for maintaining lymphoblastoid cell growth. Proc Natl Acad Sci U S A 106:4419-24
Tong, X; Drapkin, R; Yalamanchili, R et al. (1995) The Epstein-Barr virus nuclear protein 2 acidic domain forms a complex with a novel cellular coactivator that can interact with TFIIE. Mol Cell Biol 15:4735-44

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