EBV infection and direct transformation of B cells. EBV infects naive B cells through 2 surface receptors, CD21 and the class II MHC, HLA-DQ. During latency, the virus is maintained as an episome in the nucleus of infected cells, and viral genes are expressed, in the absence of lytic replication of the virus. EBV subverts normal B-cell differentiation, notably by the expression of LMP1, a viral latent protein expressed at the surface of infected cells. LMP1 associates with transduction molecules such as TRADD and TRAF and activates the NF-κB pathway in a CD40-like manner. LMP1 is required for the activation and immortalization of B cells. LMP2 is a viral transmembrane protein that associates with Lyn/Syk kinase and PI3 kinase, leading to the activation of PKC and AKT, respectively. LMP2 can substitute for signals emanating from the BCR. Both LMP1 and LMP2 converge to activate proliferation and survival pathways in EBV latently infected cells. EBNA2 transactivates LMP1 and a number of cellular genes involved in activation and proliferation. Polyclonal infected B cells proliferate and produce immortalized lymphoblastoid cell lines in vitro. In vivo, EBV-infected B cells are negatively controlled by anti-EBV cytotoxic T lymphocytes (CTLs). Failure to control EBV-infected B cells may lead to the development of posttransplantation lymphoproliferative disorder (PTLD). Additional oncogenic mutations lead to clonal selection and evolution toward monoclonal tumors such as Burkitt lymphoma (BL), Hodgkin disease (HD), and diffuse large B-cell lymphomas (DLBCLs) in immunocompromised patients.