Epstein-Barr virus (EBV) is a persistent herpesvirus that is carried latently and reactivates, usually without harm to the infected individual. EBV infects and """"""""immortalizes"""""""" or """"""""growth transforms"""""""" normal resting human B cells in vitro driving them to become latently infected proliferating lymphoblasts. The virus also plays a central role in several human diseases, including several B cell neoplasias. The goal of this proposal will be to investigate the relationship between normal B cell biology and the establishment of a latent, persistent infection by Epstein-Barr virus. Specifically, we will address two aspects of this relationship. First, we will undertake a detailed analysis of how a model B cell activation gene (Blast-1) is regulated. Blast-1 is an adhesion molecule, restricted in its expression to lymphoid and myeloid cells, that is upregulated by EBV infection. We will map the minimal promoter and the sequences responsible for tissue specific expression. We will establish the relative roles of increased transcription and mRNA stabilization in activation by EBV. Regulatory elements so defined will be mapped. The mechanism will then be compared to that of other known activators including IL-4, PMA, IL-lb and ionomycin. Second, we will study the relationship between the form of the persistent viral genome and the differentiation stage of the infected cell. Specifically, we will investigate the role of cellular activation stage in determining whether the virus persists as an episome or integrated. The viral sequences involved in episomal amplification will be investigated. Previously identified integration sites will be cloned and sequenced to investigate the mechanism of integration. Lastly, tumor cell lines will be tested for the presence of integrated EBV genomes by the fluorescence in situ hybridization technique to provide a definitive answer as to whether such sequences are or are not present.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI018757-13
Application #
3128162
Study Section
Experimental Virology Study Section (EVR)
Project Start
1981-09-01
Project End
1996-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
13
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111
Thorley-Lawson, David; Deitsch, Kirk W; Duca, Karen A et al. (2016) The Link between Plasmodium falciparum Malaria and Endemic Burkitt's Lymphoma-New Insight into a 50-Year-Old Enigma. PLoS Pathog 12:e1005331
Qiu, Jin; Smith, Pamela; Leahy, Leah et al. (2015) The Epstein-Barr virus encoded BART miRNAs potentiate tumor growth in vivo. PLoS Pathog 11:e1004561
Thorley-Lawson, David A (2015) EBV Persistence--Introducing the Virus. Curr Top Microbiol Immunol 390:151-209
Torgbor, Charles; Awuah, Peter; Deitsch, Kirk et al. (2014) A multifactorial role for P. falciparum malaria in endemic Burkitt's lymphoma pathogenesis. PLoS Pathog 10:e1004170
Qiu, Jin; Thorley-Lawson, David A (2014) EBV microRNA BART 18-5p targets MAP3K2 to facilitate persistence in vivo by inhibiting viral replication in B cells. Proc Natl Acad Sci U S A 111:11157-62
Hawkins, Jared B; Delgado-Eckert, Edgar; Thorley-Lawson, David A et al. (2013) The cycle of EBV infection explains persistence, the sizes of the infected cell populations and which come under CTL regulation. PLoS Pathog 9:e1003685
Thorley-Lawson, David A; Hawkins, Jared B; Tracy, Sean I et al. (2013) The pathogenesis of Epstein-Barr virus persistent infection. Curr Opin Virol 3:227-32
Tracy, Sean I; Kakalacheva, Kristina; Lunemann, Jan D et al. (2012) Persistence of Epstein-Barr virus in self-reactive memory B cells. J Virol 86:12330-40
Smith, Pamela A; Merritt, David; Barr, Leah et al. (2011) An orthotopic model of metastatic nasopharyngeal carcinoma and its application in elucidating a therapeutic target that inhibits metastasis. Genes Cancer 2:1023-33
Hawkins, Jared B; Jones, Mark T; Plassmann, Paul E et al. (2011) Chemotaxis in densely populated tissue determines germinal center anatomy and cell motility: a new paradigm for the development of complex tissues. PLoS One 6:e27650

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