Epstein-Barr virus-mediated dysregulation of human microRNA expression

MicroRNAs (miRNAs) are a large class of small (~22 nt) non-coding RNAs that negatively regulate gene expression most often at the level of translation, and have been shown to be key regulators in a variety of processes including development, cell cycle and immunity. The Epstein-Barr virus (EBV) is an oncogenic herpes virus endemic in humans that encodes at least twenty-two of its own miRNAs. Cellular miRNAs have well-established roles in cancer and immune pathways, and multiple cellular miRNAs directly target viral messages. Additionally, multiple viruses express suppressors of cellular RNAi-induced silencing. Here we show that EBV de novo infection of primary cultured human B-cells results in a dramatic down-regulation of cellular miRNA expression, suggesting the virus may encode or activate a suppressor of miRNA expression. We additionally show that the immuno-modulatory microRNA miR-146a, down-regulated on initial infection, is significantly up-regulated more than 100-fold upon induction of the viral lytic cycle, and appears to have inhibitory effects on the progression of the lytic cycle. Our results show that EBV has large effects on cellular miRNA expression.