The long term goal of this research is to understand the molecular mechanisms by which the Epstein-Barr virus (EBV) causes cancer. EBV is associated with nasopharyngeal carcinoma, endemic Burkitt's lymphoma (BL), and Hodgkin's lymphoma. We contend that AIDS-related lymphomas offer novel insights into EBV oncogenesis because immunosuppression unmasks properties intrinsic to the virus that may be central to its pathobiology. Identification in AIDS patients of 11 a defective EBV genome that disrupts viral latency, 2/ a unique EBV replicative lesion (oral hairy leukoplakia), and 31 lytic antigens in AIDS-related lymphomas all confirm the validity of this notion. Whereas 6 nuclear antigens and 3 membrane proteins expressed in latent infection of lymphoblastoid cells are recognized as contributing to EBV-induced lymphoproliferation, a role for replicative cycle proteins has not been appreciated. We now hypothesize that, as part of the viral replicative process, this lymphotropic herpesvirus activates site-specific recombinases involved in diversification of immunoglobulin and T cell receptor genes. Biologic consequences include generation of defective EBV genomes with novel pathogenic potential, virus integration into the host genome, and the introduction of genomic instability.
Specific aims to test this hypothesis are: II determine the EBV gene product that induces expression of recombinase activating genes l and 2 (RAG1&2); 2) evaluate the effect of V(D)J recombinase on EBV genomic organization; 3) elucidate pathogenic consequences of EBV-associated RAG expression. EBV induction of RAG expression by genes required for viral DNA replication (EBNA1 and BZLF1) will be examined in transfection assays at the RNA, protein and functional levels (aim 1). EBV and cellular DNA breakpoints from cloned integration sites in BL cells will be sequenced to determine presence of V(D)J recognition signal sequences (RSS). EBV intermolecular and intragenic rearrangements will be sequenced for hallmarks of V(D)J recombinase joining: presence of heptamer/nanomer RSS, junctional loss and addition of nucleotides (aim 2). Finally, using AIDS- related lymphomas, clinical correlations will be made by parallel analyses for integration of unit length and defective EBV DNA (aim 3). Aberrant V(D)J recombinase expression during viral DNA replication would provide the first indication that EBV reactivation in chronic virus carriers has a direct role in the oncogenic process and would provide a rationale for antiviral interventions during the severe immunosuppression of AIDS.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (SRC (20))
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Read-Connole, Elizabeth Lee
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Louisiana State University Hsc Shreveport
Schools of Medicine
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Shi, Mingxia; Gan, Yan-Jun; Davis, Timothy O et al. (2013) Downregulation of the polyamine regulator spermidine/spermine N(1)-acetyltransferase by Epstein-Barr virus in a Burkitt's lymphoma cell line. Virus Res 177:11-21
Ikuta, Kazufumi; Ding, Mingyu; Zhang, Fangfang et al. (2011) Epithelial cell retention of transcriptionally active, P3HR-1-derived heterogeneous Epstein-Barr virus DNA with concurrent loss of parental virus. J Virol 85:7634-43
Ikuta, Kazufumi; Srinivas, Shamala K; Schacker, Tim et al. (2008) Points of recombination in Epstein-Barr virus (EBV) strain P3HR-1-derived heterogeneous DNA as indexes to EBV DNA recombinogenic events in vivo. J Virol 82:11516-25
Moody, Cary A; Scott, Rona S; Amirghahari, Nazanin et al. (2005) Modulation of the cell growth regulator mTOR by Epstein-Barr virus-encoded LMP2A. J Virol 79:5499-506
Wagner, Hans-Joachim; Scott, Rona S; Buchwald, Dedra et al. (2004) Peripheral blood lymphocytes express recombination-activating genes 1 and 2 during Epstein-Barr virus-induced infectious mononucleosis. J Infect Dis 190:979-84
Moody, Cary A; Scott, Rona S; Su, Tao et al. (2003) Length of Epstein-Barr virus termini as a determinant of epithelial cell clonal emergence. J Virol 77:8555-61
Gan, Yan-Jun; Razzouk, Bassem I; Su, Tao et al. (2002) A defective, rearranged Epstein-Barr virus genome in EBER-negative and EBER-positive Hodgkin's disease. Am J Pathol 160:781-6
Chodosh, J; Gan, Y j; Holder, V P et al. (2000) Patterned entry and egress by Epstein-Barr virus in polarized CR2-positive epithelial cells. Virology 266:387-96
Slobod, K S; Taylor, G H; Sandlund, J T et al. (2000) Epstein-Barr virus-targeted therapy for AIDS-related primary lymphoma of the central nervous system. Lancet 356:1493-4
Chodosh, J; Holder, V P; Gan, Y J et al. (1998) Eradication of latent Epstein-Barr virus by hydroxyurea alters the growth-transformed cell phenotype. J Infect Dis 177:1194-201

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