ekieff@rics.bwh.harvard.edu

Brigham and Women's Hospital has released this major bulletin highlighting the efforts of Dr. Elliott Kieff and his colleague Frederick Wang, M.D., Medical Director of the BWH Clinical Virology Laboratory and respected Channing Laboratory scientist, to produce an Epstein-Barr vaccine to aid in the fight against cancer. Click HERE to read about this important new research breakthrough.

Human viruses are responsible for about 20% of human malignancies world-wide and offer unique opportunities for early diagnosis, prevention, and therapeutic intervention. Viruses have relatively simple genomes and effect nearly immediate changes in infected cell signal transduction, transcription, growth, and survival. Therefore studies of virus infection also contribute to current genetics, biochemistry, cell biology, and immunology, as well as virology. Our experiments began with the study of the fundamental mechanisms by which Epstein-Barr Virus, an important causative agent of lymphomas, Hodgkin's Disease and Naso-pharyngeal carcinoma, uniquely and efficiently causes the uncontrolled proliferation and survival of normal human B lymphocytes.

We have discovered that, the virus uses only five genes to cause B cell proliferation. These genes encode nuclear proteins that usurp control over Notch regulated cell promoters, including the c-myc promoter, and an integral membrane protein that constitutively activates CD40 signaling pathways. We are currently investigating the genetics and biochemistry of the molecular and sub-molecular processes through which the viral proteins effect changes in cell signal transduction, transcription, growth, and survival so as to validate targets that can be used in assays to identify chemical inhibitors.

Ongoing projects for fellows and students involve:
(1) Elucidation of the molecular and sub-molecular pathways by which Notch and viral proteins regulate the c-myc promoter. Structural studies of a key viral and cellular interaction site.
(2) Elucidation of the molecular and sub-molecular pathways by which CD40 and a viral protein co-stimulate cell growth and survival.
(3) Proteinomic and cell genetic screens for novel genes in the CD40 and viral protein NF-kB, Junk, and p38 pathways.
(4) Sub-molecular mechanisms by which a viral protein permits episome replication and maintenance.

Izumi KM, Cahir McFarland ED, Ting AT, Riley EA, Seed B, Kieff ED. The Epstein-Barr virus oncoprotein latent membrane protein 1 engages the tumor necrosis factor receptor-associated proteins TRADD and receptor-interacting protein (RIP) but does not induce apoptosis or require RIP for NF-kappaB activation. Mol Cell Biol. 1999 Aug;19(8):5759-67. [abstract]

Ye H, Park YC, Kreishman M, Kieff E, Wu H. The structural basis for the recognition of diverse receptor sequences by TRAF2. Mol Cell. 1999 ;4:321-30. [abstract]

Wang L, Grossman SR, Kieff E. Epstein-Barr virus nuclear protein 2 interacts with p300, CBP, and PCAF histone acetyltransferases in activation of the LMP1 promoter. Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):430-5. [abstract]

Cahir-McFarland ED, Davidson DM, Schauer SL, Duong J, Kieff E. NF-kappa B inhibition causes spontaneous apoptosis in Epstein-Barr virus-transformed lymphoblastoid cells. Proc Natl Acad Sci U S A. 2000 May 23;97(11):6055-60. [abstract]

Hung SC, Kang MS, Kieff E. Maintenance of Epstein-Barr virus (EBV) oriP-based episomes requires EBV-encoded nuclear antigen-1 chromosome-binding domains, which can be replaced by high-mobility group-I or histone H1. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1865-70. Epub 2001 Feb 6. [abstract]