Essentially all brain lymphomas, as well as many peripheral lymphomas, in AIDS patients carry the Epstein- Barr virus (EBV) genome. We hypothesize that therapeutic approaches which specifically target EBV- infected cells for destruction will be useful in treating AIDS-related lymphomas. We recently showed that expression of the cellular transcription factor, XBP-1, with agents that inhibit type II HDACs is sufficient to induce lytic EBV gene transcription. We find that XBP-1 activates the two viral immediate-early (IE) promoters, while type II HDACs directly inhibit BZLF1 transcriptional function. We propose to build upon these discoveries to identify more effective methods for inducing lytic EBV infection in tumor cells with minimal toxicity to normal cells. We have also discovered that very low level lytic EBV gene expression unexpectedly enhances the ability of early-passage lymphoblastoid cell lines to form lymphoproliferative disease in immunodeficient SCID mice, and we showed that this effect is mediated (at least in part) through release of the B-cell growth factor, IL-6. In the proposed research, we will dissect the viral and cellular regulatory pathways that determine whether EBV infection is latent versus lytic in B cells, and explore whether agents which activate XBP-1 could be used to promote lytic viral infection in lymphomas (Aim 1). We will also examine how different type 1/II HDACs affect the functions of the viral lytic proteins, BZLF1 and BRLF1, and vice versa (Aim 2). In addition, we will determine how the lytic form of viral infection affects EBV pathogenesis and lymphoma formation in the presence and absence of a functional human immune system (Aim 3). Our proposed studies may lead to novel, EBV-based strategies for treating AIDS-related lymphomas. PROJECT NARRATIVE Epstein-Barr virus is an important cause of AIDS-related lymphomas, as well as other types of malignancies. The proposed research will examine how Epstein-Barr virus can be converted from a latent to active form in tumor cells, and whether drugs that can activate the lytic form of virus can be used to treat EBV-positive tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA066519-18
Application #
8204757
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Liddell Huppi, Rebecca
Project Start
1995-02-13
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
18
Fiscal Year
2012
Total Cost
$261,708
Indirect Cost
$79,266
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Wille, Coral K; Nawandar, Dhananjay M; Panfil, Amanda R et al. (2013) Viral genome methylation differentially affects the ability of BZLF1 versus BRLF1 to activate Epstein-Barr virus lytic gene expression and viral replication. J Virol 87:935-50
Raver, Ryan M; Panfil, Amanda R; Hagemeier, Stacy R et al. (2013) The B-cell-specific transcription factor and master regulator Pax5 promotes Epstein-Barr virus latency by negatively regulating the viral immediate early protein BZLF1. J Virol 87:8053-63
Robinson, Amanda R; Kwek, Swee Sen; Kenney, Shannon C (2012) The B-cell specific transcription factor, Oct-2, promotes Epstein-Barr virus latency by inhibiting the viral immediate-early protein, BZLF1. PLoS Pathog 8:e1002516
Ma, Shi-Dong; Hegde, Subramanya; Young, Ken H et al. (2011) A new model of Epstein-Barr virus infection reveals an important role for early lytic viral protein expression in the development of lymphomas. J Virol 85:165-77
Shaffer, Donald R; Savoldo, Barbara; Yi, Zhongzhen et al. (2011) T cells redirected against CD70 for the immunotherapy of CD70-positive malignancies. Blood 117:4304-14
Robinson, Amanda R; Kwek, Swee Sen; Hagemeier, Stacy R et al. (2011) Cellular transcription factor Oct-1 interacts with the Epstein-Barr virus BRLF1 protein to promote disruption of viral latency. J Virol 85:8940-53
Hagemeier, Stacy R; Barlow, Elizabeth A; Kleman, Ariel A et al. (2011) The Epstein-Barr virus BRRF1 protein, Na, induces lytic infection in a TRAF2- and p53-dependent manner. J Virol 85:4318-29
Hagemeier, Stacy R; Dickerson, Sarah J; Meng, Qiao et al. (2010) Sumoylation of the Epstein-Barr virus BZLF1 protein inhibits its transcriptional activity and is regulated by the virus-encoded protein kinase. J Virol 84:4383-94
Bristol, Jillian A; Robinson, Amanda R; Barlow, Elizabeth A et al. (2010) The Epstein-Barr virus BZLF1 protein inhibits tumor necrosis factor receptor 1 expression through effects on cellular C/EBP proteins. J Virol 84:12362-74

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