Dr. Sugden works with Epstein-Barr Virus (EBV) because it causes several different cancers in people. EBV is a herpesvirus that causes the common, benign infectious mononucleosis, as well as lymphomas such as Burkitt's Lymphoma, most B-cell lymphomas in immunocompromised hosts, and carcinomas such as nasopharyngeal carcinoma. He studies EBV both to understand its contributions to these diseases molecularly and to develop rational means to treat them. His research focuses on two facets of EBV pivotal to its inducing and maintaining human tumors. One gene product of EBV, LMP1, mimics cellular signaling pathways but in a ligand-independent manner. Its signaling drives proliferation of EBV-infected B-cells, but at high levels inhibits that proliferation. He is dissecting the mechanisms by which LMP1 regulates its host cell both positively and negatively. He has surprisingly found that LMP1 induces the cellular unfolded protein response and autophagy in B-cells to affect its host and to regulate itself. A second gene product of EBV, EBNA1, binds several elements of EBV's origin of plasmid synthesis, oriP, to mediate the synthesis and maintenance of the viral replicon in proliferating cells. EBV's replicon replicates once per S-phase and uses the cell's DNA synthetic machinery to do so. He studies EBNA1 and oriP to elucidate the mechanisms by which EBV DNA is synthesized and segregated to daughter cells. He has developed methods to visualize plasmid replicons derived from EBV in live cells allowing us to characterize in detail EBV's mechanism of partitioning its genome to daughter cells.
These methods are being extended to Kaposi's Sarcoma Herpes Virus (KSHV), a human tumor virus related to EBV, that also maintains itself extrachromosomally. Inhibiting EBNA1 in Burkitt's Lymphoma cells leads to the loss of the viral genome from these cells and to their death by apoptosis. Inhibiting EBNA1 in tumor cells dually infected by EBV and KSHV leads to the cells' failure to proliferate clonally. He is elucidating the molecular contributions EBV provides these different tumor cells to understand them and to allow us to develop specific inhibitors of them as a means of treating these human cancers.