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.
(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.
Principle Investigator: Elliott D. Kieff, MD, PhD
Harriet Ryan Albee Professor, Department of Medicine, Brigham and Women's Hospital,
Professor, Department of Microbiology and Immunobiology, Harvard Medical School