Cytokine signaling and Epstein-Barr virus-mediated cell transformation

Epstein-Barr virus (EBV) latent infection is tightly associated with the development of lymphoid and epithelial human malignancies. The disruption of cell-growth checkpoints is mediated by a limited number of viral proteins that interfere with signal transduction mechanisms and transcription control in the infected cell. Genetic and biochemical evidence supports the notion that EBV-mediated transformation relies extensively on interference with cytokine signaling networks. This is achieved through direct modulation of cytokine receptor signaling mechanisms as well as alterations in the expression levels of various cytokines. The principal effector of these interventions is the EBV latent membrane protein 1 (LMP1) which plays a central role in the transformation process. This viral protein mimics activated receptors of the tumor necrosis factor receptor superfamily to promote cell growth and antiapoptotic mechanisms. LMP1 and other EBV latent proteins upregulate cytokines and growth factors which participate in autocrine and paracrine loops that are likely to promote cell transformation and modulate immune responses. This report will review the molecular mechanisms that underlie the disruption of cytokine signaling mechanisms in EBV-mediated transformation with a particular emphasis on the LMP1 mechanism of function.