Virology Faculty Member - Elliott Kieff

Elliott Kieff

Albee Professor of Medicine and Professor of Microbiology and Molecular Genetics

Brigham and Women's Hospital
Channing Labs, 8th Fl, Medicine/Micro
181 Longwood Ave
Boston, MA 02115
Tel: 617-525-4252
Fax: 617-525-4257
Email: ekieff@rics.bwh.harvard.edu
Visit my lab page here.



Oncogenic human viruses offer exceptional opportunities to use biochemical and genetic tools based in the causative virus to discover and interrogate cell pathways relevant to cancer. Our group studies the Epstein Barr Herpesvirus, which has long term latency in human B lymphocytes. EBV causes Infectious Mononucleosis, Lymphoproliferative Diseases, Burkitt’s Lymphoma, Hodgkin’s Disease, and anaplastic Nasopharyngeal Carcinoma. The EBV genome has 89 genes; large for a virus, but at least 300 fold less complex than the human genome. In human B lymphocytes EBV effects nearly immediate changes in infected cell transcription, signal transduction, growth, and survival. Therefore genetic and biochemical studies of EBV infection contribute new knowledge to not only to virology, but also to cell biochemistry, biology, and genetics and to immunology. Our experiments begin with studies of the fundamental mechanisms by which EBV uniquely and efficiently causes uncontrolled proliferation and survival of normal human B lymphocytes as lymphoblastoid cell lines. EBV encodes five nuclear protein genes (EBNA2, EBNALP, EBNA3A, EBNA3C, and EBNA1) and 1 integral membrane protein (LMP1), which are the essential proteins for efficient B cell proliferation and survival. EBNA1 is also essential for EBV episome persistence, whereas EBNA2 and EBNALP initially coordinately activate virus and cell gene transcription. EBNA3A and EBNA3C modulate these affects. EBNA2, EBNALP, EBNA3A, and EBNA3C usurp control of Notch regulated cell promoters, including the c-myc promoter. This pathway is notably important in lymphocyte growth, lymphoma, leukemia and other malignancies. LMP1 constitutively activates CD40 signaling pathways and studies of LMP1 inform signaling and cell survival effects downstream of TNF receptors. LMP2, a second integral membrane protein expressed in latent EBV infection in lymphoblastoid cells is important for transformation of lymphocytes that lack membrane Ig induced cell survival. We use genetics, biochemistry, and systems biology to study the molecular and sub-molecular processes with a goal of identifying critical protein targets to interrupt lymphocyte signal transduction, transcription, growth, or cell survival. Systems biology approaches enable us to develop knowledge of the interaction and dependency of EBV genes on specific genes from the complete human genome. We then use this knowledge to identify chemicals that have specific affects on target cell proteins.

Ongoing projects for fellows and students include (i) Elucidation of the molecular and sub-molecular pathways by which EBNA2, EBNALP, EBNA3A and EBNA3C and Notch regulate and remodel transcription regulatory sites. (ii) Elucidation of the molecular and sub-molecular pathways by which LMP1, CD40, and LMP2 co-stimulate cell growth and survival. (iii) Elucidation of the mechanisms by which EBNA1 enable episome replication and persistence. (iv) Systems biology based genetic and reverse genetic analyses of the effects of EBV replication, packaging and envelopment on the cell treanscription, proteome, and metabolome. (v) Role of EBV encoded micro RNAs in latency and replication.













Last Update: 12/4/2014



Publications

1. Zhao B, Barrera LA, Ersing I, Willox B, Schmidt SC, Greenfeld H, Zhou H, Mollo SB, Shi TT, Takasaki K, Jiang S, Cahir-McFarland E, Kellis M, Bulyk ML, Kieff E, Gewurz BE. The NF-?B Genomic Landscape in Lymphoblastoid B Cells. Cell Rep. 2014 Sep 11; 8(5):1595-606.
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2. Lee EK, Kim SY, Noh KW, Joo EH, Zhao B, Kieff E, Kang MS. Small molecule inhibition of Epstein-Barr virus nuclear antigen-1 DNA binding activity interferes with replication and persistence of the viral genome. Antiviral Res. 2014 Apr; 104:73-83.
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3. Jiang S, Willox B, Zhou H, Holthaus AM, Wang A, Shi TT, Maruo S, Kharchenko PV, Johannsen EC, Kieff E, Zhao B. Epstein-Barr Virus Nuclear Antigen 3C binds to BATF/IRF4 or SPI1/IRF4 composite sites and recruits Sin3A to repress CDKN2A. Proc Natl Acad Sci U S A. 2014 Jan 7; 111(1):421-6.
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4. Chen YL, Liu CD, Cheng CP, Zhao B, Hsu HJ, Shen CL, Chiu SJ, Kieff E, Peng CW. Nucleolin is important for Epstein-Barr virus nuclear antigen 1-mediated episome binding, maintenance, and transcription. Proc Natl Acad Sci U S A. 2014 Jan 7; 111(1):243-8.
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5. Kim JE, Kim SY, Lim SY, Kieff E, Song YJ. Role of Ca2+/Calmodulin-Dependent Kinase II-IRAK1 Interaction in LMP1-Induced NF-?B Activation. Mol Cell Biol. 2014 Feb; 34(3):325-34.
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6. Portal D, Zhou H, Zhao B, Kharchenko PV, Lowry E, Wong L, Quackenbush J, Holloway D, Jiang S, Lu Y, Kieff E. Epstein-Barr virus nuclear antigen leader protein localizes to promoters and enhancers with cell transcription factors and EBNA2. Proc Natl Acad Sci U S A. 2013 Nov 12; 110(46):18537-42.
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7. Zhou X, Gewurz BE, Ritchie JM, Takasaki K, Greenfeld H, Kieff E, Davis BM, Waldor MK. A Vibrio parahaemolyticus T3SS effector mediates pathogenesis by independently enabling intestinal colonization and inhibiting TAK1 activation. Cell Rep. 2013 May 30; 3(5):1690-702.
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8. Liu CD, Cheng CP, Fang JS, Chen LC, Zhao B, Kieff E, Peng CW. Modulation of Epstein-Barr virus nuclear antigen 2-dependent transcription by protein arginine methyltransferase 5. Biochem Biophys Res Commun. 2013 Jan 18; 430(3):1097-102.
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9. Liu CD, Chen YL, Min YL, Zhao B, Cheng CP, Kang MS, Chiu SJ, Kieff E, Peng CW. The nuclear chaperone nucleophosmin escorts an Epstein-Barr Virus nuclear antigen to establish transcriptional cascades for latent infection in human B cells. PLoS Pathog. 2012; 8(12):e1003084.
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10. Rozenblatt-Rosen O, Deo RC, Padi M, Adelmant G, Calderwood MA, Rolland T, Grace M, Dricot A, Askenazi M, Tavares M, Pevzner SJ, Abderazzaq F, Byrdsong D, Carvunis AR, Chen AA, Cheng J, Correll M, Duarte M, Fan C, Feltkamp MC, Ficarro SB, Franchi R, Garg BK, Gulbahce N, Hao T, Holthaus AM, James R, Korkhin A, Litovchick L, Mar JC, Pak TR, Rabello S, Rubio R, Shen Y, Singh S, Spangle JM, Tasan M, Wanamaker S, Webber JT, Roecklein-Canfield J, Johannsen E, Barabási AL, Beroukhim R, Kieff E, Cusick ME, Hill DE, Münger K, Marto JA, Quackenbush J, Roth FP, DeCaprio JA, Vidal M. Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature. 2012 Jul 26; 487(7408):491-5.
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11. Kim SY, Song KA, Kieff E, Kang MS. Small molecule and peptide-mediated inhibition of Epstein-Barr virus nuclear antigen 1 dimerization. Biochem Biophys Res Commun. 2012 Jul 27; 424(2):251-6.
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12. Gewurz BE, Towfic F, Mar JC, Shinners NP, Takasaki K, Zhao B, Cahir-McFarland ED, Quackenbush J, Xavier RJ, Kieff E. Genome-wide siRNA screen for mediators of NF-?B activation. Proc Natl Acad Sci U S A. 2012 Feb 14; 109(7):2467-72.
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13. Geiser V, Cahir-McFarland E, Kieff E. Latent membrane protein 1 is dispensable for Epstein-Barr virus replication in human embryonic kidney 293 cells. PLoS One. 2011; 6(8):e22929.
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14. Zhao B, Zou J, Wang H, Johannsen E, Peng CW, Quackenbush J, Mar JC, Morton CC, Freedman ML, Blacklow SC, Aster JC, Bernstein BE, Kieff E. Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth. Proc Natl Acad Sci U S A. 2011 Sep 6; 108(36):14902-7.
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15. Wang H, Zou J, Zhao B, Johannsen E, Ashworth T, Wong H, Pear WS, Schug J, Blacklow SC, Arnett KL, Bernstein BE, Kieff E, Aster JC. Genome-wide analysis reveals conserved and divergent features of Notch1/RBPJ binding in human and murine T-lymphoblastic leukemia cells. Proc Natl Acad Sci U S A. 2011 Sep 6; 108(36):14908-13.
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16. Xing L, Kieff E. cis-Acting effects on RNA processing and Drosha cleavage prevent Epstein-Barr virus latency III BHRF1 expression. J Virol. 2011 Sep; 85(17):8929-39.
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17. Gewurz BE, Mar JC, Padi M, Zhao B, Shinners NP, Takasaki K, Bedoya E, Zou JY, Cahir-McFarland E, Quackenbush J, Kieff E. Canonical NF-kappaB activation is essential for Epstein-Barr virus latent membrane protein 1 TES2/CTAR2 gene regulation. J Virol. 2011 Jul; 85(13):6764-73.
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18. Verweij FJ, van Eijndhoven MA, Hopmans ES, Vendrig T, Wurdinger T, Cahir-McFarland E, Kieff E, Geerts D, van der Kant R, Neefjes J, Middeldorp JM, Pegtel DM. LMP1 association with CD63 in endosomes and secretion via exosomes limits constitutive NF-?B activation. EMBO J. 2011 Jun 1; 30(11):2115-29.
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19. Portal D, Zhao B, Calderwood MA, Sommermann T, Johannsen E, Kieff E. EBV nuclear antigen EBNALP dismisses transcription repressors NCoR and RBPJ from enhancers and EBNA2 increases NCoR-deficient RBPJ DNA binding. Proc Natl Acad Sci U S A. 2011 May 10; 108(19):7808-13.
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20. Calderwood MA, Lee S, Holthaus AM, Blacklow SC, Kieff E, Johannsen E. Epstein-Barr virus nuclear protein 3C binds to the N-terminal (NTD) and beta trefoil domains (BTD) of RBP/CSL; only the NTD interaction is essential for lymphoblastoid cell growth. Virology. 2011 May 25; 414(1):19-25.
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21. Maruo S, Zhao B, Johannsen E, Kieff E, Zou J, Takada K. Epstein-Barr virus nuclear antigens 3C and 3A maintain lymphoblastoid cell growth by repressing p16INK4A and p14ARF expression. Proc Natl Acad Sci U S A. 2011 Feb 1; 108(5):1919-24.
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22. Kang MS, Lee EK, Soni V, Lewis TA, Koehler AN, Srinivasan V, Kieff E. Roscovitine inhibits EBNA1 serine 393 phosphorylation, nuclear localization, transcription, and episome maintenance. J Virol. 2011 Mar; 85(6):2859-68.
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23. Zhao B, Mar JC, Maruo S, Lee S, Gewurz BE, Johannsen E, Holton K, Rubio R, Takada K, Quackenbush J, Kieff E. Epstein-Barr virus nuclear antigen 3C regulated genes in lymphoblastoid cell lines. Proc Natl Acad Sci U S A. 2011 Jan 4; 108(1):337-42.
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24. Boehm D, Gewurz BE, Kieff E, Cahir-McFarland E. Epstein-Barr latent membrane protein 1 transformation site 2 activates NF-kappaB in the absence of NF-kappaB essential modifier residues 133-224 or 373-419. Proc Natl Acad Sci U S A. 2010 Oct 19; 107(42):18103-8.
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25. Lee S, Sakakibara S, Maruo S, Zhao B, Calderwood MA, Holthaus AM, Lai CY, Takada K, Kieff E, Johannsen E. Epstein-Barr virus nuclear protein 3C domains necessary for lymphoblastoid cell growth: interaction with RBP-Jkappa regulates TCL1. J Virol. 2009 Dec; 83(23):12368-77.
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26. Maruo S, Wu Y, Ito T, Kanda T, Kieff ED, Takada K. Epstein-Barr virus nuclear protein EBNA3C residues critical for maintaining lymphoblastoid cell growth. Proc Natl Acad Sci U S A. 2009 Mar 17; 106(11):4419-24.
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27. Fernandez AF, Rosales C, Lopez-Nieva P, Graña O, Ballestar E, Ropero S, Espada J, Melo SA, Lujambio A, Fraga MF, Pino I, Javierre B, Carmona FJ, Acquadro F, Steenbergen RD, Snijders PJ, Meijer CJ, Pineau P, Dejean A, Lloveras B, Capella G, Quer J, Buti M, Esteban JI, Allende H, Rodriguez-Frias F, Castellsague X, Minarovits J, Ponce J, Capello D, Gaidano G, Cigudosa JC, Gomez-Lopez G, Pisano DG, Valencia A, Piris MA, Bosch FX, Cahir-McFarland E, Kieff E, Esteller M. The dynamic DNA methylomes of double-stranded DNA viruses associated with human cancer. Genome Res. 2009 Mar; 19(3):438-51.
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28. Choy E, Yelensky R, Bonakdar S, Plenge RM, Saxena R, De Jager PL, Shaw SY, Wolfish CS, Slavik JM, Cotsapas C, Rivas M, Dermitzakis ET, Cahir-McFarland E, Kieff E, Hafler D, Daly MJ, Altshuler D. Genetic analysis of human traits in vitro: drug response and gene expression in lymphoblastoid cell lines. PLoS Genet. 2008 Nov; 4(11):e1000287.
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29. Song YJ, Izumi KM, Shinners NP, Gewurz BE, Kieff E. IRF7 activation by Epstein-Barr virus latent membrane protein 1 requires localization at activation sites and TRAF6, but not TRAF2 or TRAF3. Proc Natl Acad Sci U S A. 2008 Nov 25; 105(47):18448-53.
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30. Kang MS, Soni V, Bronson R, Kieff E. Epstein-Barr virus nuclear antigen 1 does not cause lymphoma in C57BL/6J mice. J Virol. 2008 Apr; 82(8):4180-3.
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