The growth transformation of human B cells by Epstein-Barr virus (EBV) is controlled by the coordinate expression of 10 latent viral genes. This transforming capacity is believed to be fundamental to the involvement of the virus in human malignancies of B cell origin. EBV-negative Burkitt's lymphoma (dG75) clones stably expressing one of these EBV-coded antigens, EBNA-4, have been established using an episomal-based plasmid. EBNA-4 expression was found to upregulate the cytoskeletal protein vimentin as well as surface expression of the activation antigen CD40. In addition, the presence of EBNA-4 resulted in downregulation of the Burkitt's lymphoma-associated antigen (BLA/CD77). These studies show for the first time that EBNA-4 modulates the expression of several cellular genes implicated in cell-growth transformation.