The hypothesis driving this work is that Epstein-Barr virus (EBV) transactivators are essential for EBV-induced malignancies. The goal of our work is uncovering the mechanisms whereby these transactivators function. We study the complex regulation of Epstein-Barr virus nuclear antigen (EBNA) expression during EBV infection. EBNA proteins contribute to the immortalization of B lymphocytes, and thus may have a role in the genesis of EBV-associated lymphomas. Another project involves the EBV lytic cycle protein, Z, and the cellular proto-oncogene, c-myb. The Z protein is responsible for initiating the switch from EBV latency to lytic infection. We have discovered that c-Myb markedly enhances the ability of Z to activate viral gene expression. Thus we are determining the mechanism of synergy between Z and c-Myb. We are collaboratively studying the regulation of Z expression using a SCID mouse model of immunosuppression-associated lymphomagenesis.