's abstract): Epstein-Barr virus is a pathogenic human herpesvirus that persists for the lifetime of the host. Recently, resting memory B cells, that express the viral latent gene LMP 2, have been identified as a site of persistence. How these cells are produced and maintained is unknown. This stands in stark contrast to the behavior of the virus in vitro where it is known to be a powerful immortalizing virus encoding at least nine latent proteins that include known growth promoting genes and oncogenes. The hypothesis is that EBV-infected B cells are maintained like normal B cells with the resting cells circulating in the periphery and the proliferating blasts being retained within the lymphoid tissue. This implies that the numbers of circulating cells must be replenished through proliferation in lymphoid tissue. The goals of this study are to understand: 1. How EBV can affect the transitions from a proliferating to a resting cell and thereby gain access to and persist in the memory B cell compartment. 2. How and via which latency states the infected memory B cells replace and maintain their numbers. 3. How this system is perturbed in immunosuppressed individuals. To achieve this goal the applicant will: 1. Identify the infected cell types found in mucosal lymphoid tissue and arising in the periphery of immunosuppressed patients using DNA PCR to identify the virus and monoclonal antibodies that distinguish discrete populations of mature B cells. 2. Use monoclonal antibodies, magnetic beads and the FACS to isolate the different populations of infected cells and test them for latent gene expression using RT PCR and for viral replication using Gardella gels. 3. Test if different forms of latent infection (latency 0,1,2 and 3 for example) can give rise to each other by tracing infected cells in vivo using a marker of clonal relatedness and by observing the effects of cellular signaling on the state of viral latency. 4. Use mouse model systems to study how LMP2 positive cells may escape immunosurveillance (LMP2 transgenics), and identify the potentially oncogenic populations in immunosuppressed donors (SCID mice).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI018757-17
Application #
2837366
Study Section
Virology Study Section (VR)
Program Officer
Beisel, Christopher E
Project Start
1981-09-01
Project End
2002-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
17
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Tufts University
Department
Pathology
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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