Samuel H. Speck, Ph.D., associate professor of pathology and of molecular microbiology, has received a five-year $1.5 million grant from the National Cancer Institute. The funding will support his studies of the Epstein-Barr virus (EBV), which causes mononucleosis and several cancers.
Once people contract EBV, they remain infected for the rest of their lives, usually with few symptoms. But the virus is associated with the development of Burkitt's lymphoma in equatorial Africa and nasopharyngeal carcinoma in southern China. More recently, it has been linked to B-cell and T-cell lymphomas, Hodgkin's disease, thymic tumors and gastric cancer.
The virus can remain quiescent inside antibody-producing cells called B cells, occasionally reproducing its genetic material. Or it can suddenly become active, giving rise to new virus particles that burst their way out of cells. Speck is interested in how the virus chooses between these two options.
"A potential use of this research is to develop strategies to interfere with viral reactivation and replication," he said. "This might prevent the spread of the virus from individual to individual and perhaps prevent reactivation within a single person."
Speck's research focuses on a molecular switch that keeps the virus dormant when turned off and makes the virus replicate when turned on. The switch controls expression of a gene called BZLF1, which codes for a protein called ZEBRA. This protein triggers the cascade of events that results in viral replication.
The molecular switch that regulates the expression of ZEBRA is a stretch of DNA, called a promoter, that precedes the BZLF1 gene. It contains several short sequences or cis elements. When certain host proteins contact these elements, they flick the switch to off or on.
Speck has identified several cis elements in the BZLF1 promoter and several host proteins that bind to them. The new grant will enable him to determine which of these cellular regulatory proteins are important and which pathways activate those proteins in response to events at the cell surface. For example, aggregation of antibody molecules present on the surface of infected B cells can trigger viral replication in certain cultured EBV-infected cells.
Speck also will investigate the regulation of a gene called BRLF1, which is adjacent to the BZLF1 gene. The protein encoded by BRLF1 acts in concert with ZEBRA to trigger viral replication.
"A detailed understanding of how viral reactivation is controlled is essential for understanding maintenance of latency," Speck said.
