MERIT Award Recipient: S. Diane Hayward, Ph.D.
Regulation of Replication and Latency by EBV EBNAs
The herpesvirus Epstein-Barr virus infects >85% of the population and establishes a latent infection in B cells that is maintained for the life of the individual. The combination of long-term latent infection and the ability of Epstein-Barr virus to disregulate cellular growth control can lead to the development of Epstein-Barr virus-associated cancers. Immunosuppressed individuals such as transplant recipients and AIDS patients are particularly at risk. Epstein-Barr virus is associated with post transplant lymphoproliferative disease, primary central nervous system lymphoma and B cell lymphoma in AIDS, Burkitt lymphoma, nasopharyngeal carcinoma and a proportion of Hodgkin's lymphomas and gastric carcinomas.
The goal of Dr. Hayward's research program is to identify and characterize the cellular signaling pathways that are manipulated by Epstein-Barr virus to stimulate cell proliferation. One of the key contributions made by this laboratory was the discovery that early events in Epstein-Barr virus infection mimic aspects of the cellular Notch pathway. Activation of Notch signaling reprograms cellular gene expression by overcoming repression mediated by the cell DNA binding protein CBF1. Dr. Hayward's group found that the viral EBNA2 protein acts analogously to Notch in activating CBF1-repressed genes.
Currently, gene array technologies are being exploited to determine how much of the transcriptional reprogramming mediated by Notch is also mediated by EBNA2. Identification of cell genes whose expression is specifically changed by EBNA2 will provide a necessary base of information on which to draw for the design of anti-viral therapeutic approaches to the treatment of Epstein-Barr virus-associated cancers. Genetic mutations are known to alter Notch signaling in some other cancers, and Dr. Hayward's studies also have the potential to impact on these non-virus-associated cancers. Growth regulatory proteins whose expression is altered by both Notch and EBNA2 would be strong candidates for proteins with a cancer-potentiating role. Peptide inhibitors are also being developed to block the interaction between EBNA2 and CBF1. These reagents would have clinical application in the control of post-transplant lymphoproliferative disease.