Elliott D. Kieff
Department of Medicine
Department of Microbiology and Molecular Genetics
Programs in Virology, Biomedical Sciences, and Immunology
Brigham and Women's Hospital
Channing Laboratory
181 Longwood Avenue, Room 865
Boston, MA, 02115
Tel: (617) 525-4252
Fax:(617) 525-4257
Email: ekieff@rics.bwh.harvard.edu
10 postdoctoral fellows, 2 graduate students
Our group studies the Epstein Barr Herpesvirus, which has long term latency in human B lymphocytes and causes Infectious Mononucleosis, Lymphoproliferative Diseases, Burkitt’s Lymphoma, ~50% of Hodgkin’s Disease, and anaplastic Nasopharyngeal Carcinoma. Oncogenic human viruses offer exceptional opportunities to investigate cell pathways relevant to cancer, using biochemical tools and genetics based in the causative virus. The EBV genome has 89 genes; large for a virus but at least 400 fold less complex than the diploid human genome. EBV effects nearly immediate changes in infected cell signal transduction, transcription, growth, and survival. Therefore genetic and biochemical studies of virus 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 Epstein-Barr Virus uniquely and efficiently causes the 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 essential for EBV episome persistence, where as EBNA2 and EBNALP initially coordinately activate virus and cell gene transcription and EBNA3A and EBNA3C modulate these affects. EBNA2, EBNALP, EBNA3A, and EBNA3C usurp control of Notch regulated cell promoters, including the c-myc promoter, providing evidence for the central importance of this pathway in leukemia and other malignancies. LMP1 constitutively activates CD40 signaling pathways and studies of LMP1 inform signaling and cell survival effects downstream of TNF receptors. We are currently investigating the genetics and biochemistry of the molecular and sub-molecular processes through which the viral proteins effect changes in lymphocyte signal transduction, transcription, growth, and survival and using validated targets to identify chemicals that have specific affects on these pathways. We also contribute to National Biodefense in deriving Vaccinia Virus strains from VVwyeth, but deleted for genes that inhibit interferon gamma, IL18, and complement responses to achieve enhanced safety in experimental models and human clinical trials.
Ongoing projects for fellows and students involve (i) Elucidation of the molecular and sub-molecular pathways by which EBNA2, EBNALP, EBNA3A and EBNA3C and Notch regulate and remodel transcriptional 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 Sub-molecular mechanisms by which EBNA1 permits episome replication and persistence. (iv) Systems biology based genetic and reverse genetic analyses of the effects of EBV replication, packaging and envelopment on the cellular proteome and transcriptome. (v) Role of EBV encoded micro RNAs in latency and replication. (6) Role of VV immune modulators in vaccine virulence.
References:
- Rosendorff A, Sakakibara S, Lu S, Kieff E, Xuan Y, DiBacco A, Shi Y, Shi Y, Gill G. NXP-2 association with SUMO-2 depends on lysines required for transcriptional repression. Proc Natl Acad Sci U S A. 103(14):5308-13, 2006;Epub 2006 Mar 27.
- Chen A, Zhao B, Kieff E, Aster JC, Wang F. EBNA-3B- and EBNA-3C-Regulated Cellular Genes in Epstein-Barr Virus-Immortalized Lymphoblastoid Cell Lines. J Virol. 80(20):10139-50. 2006
- Portal D, Rosendorff A, and Kieff E. EBNALP co-activates transcription through interaction with Histone Deacetylase 4. Proc Natl Acad Sci U S A.103(51):19278-83. 2006.
- Calderwood MA, Venkatesan 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. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7606-11. Epub 2007 Apr 19.
BBS webpage updated 12/02/2009