E pstein-Barr virus (EBV) is an oncovirus that infects B cells and epithelial cells (1-3). EBV establishes lifelong latency in memory B lymphocytes; periodic activation into the lytic cycle can lead to asymptomatic shedding of virus in saliva. Upon infection of primary B cells, EBV must first drive cell proliferation in order to establish latency (3). Latency contributes to viral persistence. Although most of mankind is persistently infected with EBV, only a small fraction develops EBV-related cancers of B and epithelial cells (3,4). While this propensity for development of cancer, particularly posttransplant lymphoproliferative disorders, is prominently associated with loss of EBV-directed T cell immunity (3,5,6), the pathogenesis of other forms of EBV-cancers, such as endemic Burkitt lymphoma and nasopharyngeal cell carcinoma, is more complex. Not surprisingly, the contribution of host cellular proteins toward EBV-driven cell proliferation and potentially to EBV-related diseases is important (3, 7-9). Most of our understanding of the involvement of cellular proteins and mechanisms that may contribute to pathogenesis derives from investigations on downstream effects of EBV latent membrane proteins and the nuclear antigens (7,8). Such studies have included new infection of B cells in culture, examination of EBV-derived B cell lines (lymphoblastoid cell lines [LCL]), and expression of individual viral proteins in culture. We are interested in understanding whether EBV can manipulate the host during the early stages of infection, possibly even before viral latency proteins are expressed.Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is well known for its prosurvival and proproliferative functions (10-13). STAT3 is also constitutively active in many human cancers, including EBV-related cancers (11,(13)(14)(15). While STAT3 can be transcriptionally induced by the EBV oncoprotein LMP1 in already transformed B cells (16), whether STAT3 contributes to cell proliferation early after infection of primary B cells with EBV has not been investigated. Anecdotally, we have observed that B cells from patients with autosomal dominant hyper-IgE syndrome (AD-HIES or Job's syndrome) are difficult to transform with EBV. Patients with AD-HIES have a heterozygous dominant negative mutation in their STAT3 gene that renders the majority of cellular STAT3 nonfunctional despite normal levels of STAT3 protein (17). Such patients have a rare primary immunodeficiency characterized by eczema, skin and lung infections, extremely elevated serum IgE, and a variety of skeletal, connective tissue, and vascular abnormalities (18). In the setting of EBV infection in culture, we have observed that LCL from AD-HIES patients are slower to emerge than those from healthy subjects, but sometimes LCL cannot be generated even after repeated attempts, suggesting that there are inherent differences between B cells derived from AD-HIES patients and those from healthy subjects. Also of importance, studies have demonst...