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



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: 10/22/2013



Publications

Johannsen E, Luftig M, Chase MR, Weicksel S, Cahir-McFarland E, Illanes D, Sarracino D, Kieff E. Proteins of purified Epstein-Barr virus. Proc Natl Acad Sci U S A. 2004 Nov 16;101(46):16286-91.

Maruo, S., Johannsen, E., Illanes, D., Cooper, A. Zhao, B., Kieff E. Epstein-Barr virus nuclear protein 3A domains essential for growth of lymphoblasts: transcriptional regulation through RBP-Jkappa/CBF1 is critical. J Virol. 79:10171-9, 2005

Zhao B, Maruo S, Cooper A, R Chase M, Johannsen E, Kieff E, Cahir-McFarland E. RNAs induced by Epstein-Barr virus nuclear antigen 2 in lymphoblastoid cell lines. Proc Natl Acad Sci U S A. 103:1900-5. 2006 Epub 2006 Jan30.

Yuan J, Cahir-McFarland E, Zhao B, Kieff E. Virus and cell RNAs expressed during Epstein-Barr virus replication. J Virol. 80:2548-65, 2006 Song YJ, Jen KY, Soni V, Kieff E, Cahir-McFarland E. IL-1 receptor-associated kinase 1 is critical for latent membrane protein 1-induced p65/RelA serine 536 phosphorylation and NF-{kappa}B activation. PNAS. 103 (8):2689-94. 2006. Epub 2006 Feb 13

Portal D, Rosendorff A, and Kieff E. EBNALP co-activates transcription through interaction with HDAC 4. PNAS.103:19278-83. 2006. Calderwood, M., K, Xing L, Chase MR, Vazquez A, Holthaus AM, Ewence AE, Li N, Hirozane-Kishikawa T, Hill DE, Vidal M, Kieff E, Johannsen E. Epstein-Barr virus and virus human protein interaction maps. PNAS. 7606-11. 2007

Song, Y. J., Izumi, K. M.,Shinners, N. P., Gewurz, B. E., Kieff, E., IRF7 activation by Epstein-Barr virus latent membrane protein 1 requires localization at activation sites and TRAF6, but not TRAF2 or TRAF3. PNAS. 18448-53. 2008

Maruo, S., Wu, Y., Ito, T., Kanda, T., Kieff, E. D., Takada, K. Epstein-Barr virus nuclear protein EBNA3C residues critical for maintaining lymphoblastoid cell growth. PNAS. 106: 4419-24. 2009

Lee, S., Sakakibara, S., Maruo, S., Zhao, B., Calderwood, M. A., Holthaus, A. M., Lai, C. Y., 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.Virology. 83: 12368-77. 2009

Fernandez, A. F., Rosales, C., Lopez-Nieva, P., Grana, O., Ballestar, E., Ropero, S., Espada, J., Melo, S. A., Lujambio, A., Fraga, M. F., Pino, G., Quer, J., et. al. , Cahir-McFarland, E., Kieff, E., Esteller, M., The dynamic DNA methylomes of double-stranded DNA viruses associated with human cancer. Genome Res. 19. 438-451, 2009



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