Epstein–Barr virus (EBV), a gamma herpesvirus persisting in B cells of most adults, is the prototypic human tumor virus. Persistent infection associates with malignancies and proliferative syndromes mainly affecting lymphoid and epithelial tissues (Rickinson and Kieff, 1996). EBV was discovered after Denis Burkitt, working in Africa in the 1950s, proposed that an infectious agent was involved in the etiology of a childhood tumor, now known as Burkitt’s lymphoma (Burkitt, 1962). Herpesvirus-like particles were subsequently observed on electron microscopic examination of cell lines derived from these tumors (Epstein et al., 1964). In lymphoid tissues EBV-associated tumors include Burkitt’s lymphoma, Hodgkin’s disease, and certain adult T-cell lymphomas. EBV infection associates with the epithelial disorders nasopharyngeal carcinoma, gastric carcinoma, and oral hairy leukoplakia (Osato and Imai, 1996; Rickinson and Kieff, 1996), the latter occurring in immunocompromised patients. In this group the presence of EBV also associates with lymphoproliferative diseases and with leiomyosarcoma, a tumor of smooth muscle origin. EBV genomes and gene expression have been detected in breast cancers (Bonnet et al., 1999; Labrecque et al., 1995). Evidence for this association, eg, detection of viral genomes in each malignant cell within a tumor, has been reviewed recently by Cohen (2000). As exhibited by the range of pathology described above, EBV clearly gains entry to a variety of cell types, notably B cells and epithelial cells. Studies of EBV biology have been facilitated by construction of viruses containing drug resistance markers, for example that described by Shimizu et al.(1996). A recent enhancement of this approach is development of viruses carrying reporter genes, such as that designated EBfaV–GFP (Speck et al., 1999; Speck and Longnecker, 1999), which bears the gene for enhanced green fluorescent protein (EGFP) and produces infectious virus in high titer. Use of this reagent enables the ready visualization and enumeration of infected cells. The strategies EBV has evolved to enter its various target cells are complex and incompletely understood. However, evidence is accumulating that entry of EBV, like many other viruses, involves interactions between several viral glycoproteins and multiple cellular entry mediators.

EBV readily infects human B cells in vitro, with initial attachment mediated by binding (Fig. 1) of the EBV major outer envelope glycoprotein, gp350/220, with cellular CD21 (Nemerow et al., 1985; reviewed in Kieff, 1996). Induction of high-level expression of CD21 on normally uninfectable cells such as mouse L cells, human T or erythroleukemia cells, or transformed epithelial cells leads to viral adsorption and inefficient infection (Ahearn