Epstein-Barr virus is a herpesvirus that infects >90% of the human population. It has two distinguishing characteristics. First it is able to maintain a life long persistent infection in healthy hosts and second it is associated with several human lymphomas and carcinomas. This proposal will address central issues related to these two properties. Persistence: EBV establishes a persistent latent infection in memory B cells. Much is known about how it does this but less is known about how the latently infected cell produces infectious virus to spread to other hosts. Our preliminary data indicate that the signal for viral replication is the terminal differentiation of the latently infected cell into a plasma cell. We will use standard molecular biological tools to identify the role of plasma cell specific transcription factors in activating the EBV lytic cycle. Since plasma cells replicate the virus only when they are fully differentiated it is likely that they release infectious virus when they migrate to the bone marrow. This would result in early B cell progenitors becoming infected. These cells could also provide a site of life time persistent infection. Therefore, the second aim of this study will be to test the role of the bone marrow as a second site of viral persistence. This will be achieved by fractionating the bone marrow into the known subsets of B cells and testing for the presence of the virus by quantitative DNA and RT PCR techniques that we have developed. Neoplasia: One of the commonest tumors associated with EBV is nasopharyngeal carcinoma. There remains little known about the molecular basis of this tumor and its association with EBV. We will use Affymetrix chip technology to provide a molecular genetic definition of NPC that distinguishes Type II and Type III (poorly and undifferentiated NPC) and tumors negative and positive for the EBV encoded oncogene LMP1. Our preliminary data demonstrates the feasibility of this approach. This analysis will identify candidate marker genes for the different types of NPC and test their roles in in vitro and in vivo models. Specifically this approach will be used to identify genes and signaling pathways activated by LMP1. This will provide a molecular basis for explaining the role of LMP1 in NPC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA065883-13
Application #
7214767
Study Section
Virology Study Section (VR)
Program Officer
Daschner, Phillip J
Project Start
1995-01-25
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
13
Fiscal Year
2007
Total Cost
$304,530
Indirect Cost
Name
Tufts University
Department
Pathology
Type
Schools of Medicine
DUNS #
039318308
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
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
Qiu, Jin; Cosmopoulos, Katherine; Pegtel, Michiel et al. (2011) A novel persistence associated EBV miRNA expression profile is disrupted in neoplasia. PLoS Pathog 7:e1002193

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