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 Aim 1, we will examine how XBP-1 and different HDACs modulate the level of lytic EBV gene expression, and determine if XBP-1 inducing agents can improve lytic induction strategies.
In Aim 2, we will determine whether lytic EBV infection enhances, or inhibits, the development of EBV-induced lymphomas in the context of a reconstituted human immune system.
In Aim 3, we will determine if T cells directed against lytic viral antigens can enhance the effectiveness of lytic induction therapies, and examine which lytic induction strategies are most effective/least toxic for inhibiting peritoneal lymphomas in SCID mice. Our proposed studies may lead to novel, EBV-based strategies for treating AIDS-related lymphomas.

Public Health Relevance

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 #
5R01CA066519-17
Application #
8010201
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Liddell Huppi, Rebecca
Project Start
1995-02-13
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
17
Fiscal Year
2011
Total Cost
$261,710
Indirect Cost
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
Kenney, Shannon C; Mertz, Janet E (2014) Regulation of the latent-lytic switch in Epstein-Barr virus. Semin Cancer Biol 26:60-8
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; Yu, Xianming; Mertz, Janet E et al. (2012) An Epstein-Barr Virus (EBV) mutant with enhanced BZLF1 expression causes lymphomas with abortive lytic EBV infection in a humanized mouse model. J Virol 86:7976-87
Hagemeier, Stacy R; Barlow, Elizabeth A; Meng, Qiao et al. (2012) The cellular ataxia telangiectasia-mutated kinase promotes epstein-barr virus lytic reactivation in response to multiple different types of lytic reactivation-inducing stimuli. J Virol 86:13360-70
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
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
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
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

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