a viral microrna cluster strongly potentiates the transforming properties of a human herpesvirus微rna病毒集群强烈强化改造人类疱疹病毒的性质.pdfVIP

A Viral microRNA Cluster Strongly Potentiates the Transforming Properties of a Human Herpesvirus 1 2 1 1 1 2 Regina Feederle , Sarah D. Linnstaedt , Helmut Bannert , Helge Lips , Maja Bencun , Bryan R. Cullen , Henri-Jacques Delecluse1* 1 Department of Virus Associated Tumours, German Cancer Research Center, Heidelberg, Germany, 2 Center for Virology and Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America Abstract Epstein-Barr virus (EBV), an oncogenic human herpesvirus, induces cell proliferation after infection of resting B lymphocytes, its reservoir in vivo. The viral latent proteins are necessary for permanent B cell growth, but it is unknown whether they are sufficient. EBV was recently found to encode microRNAs (miRNAs) that are expressed in infected B cells and in some EBV- associated lymphomas. EBV miRNAs are grouped into two clusters located either adjacent to the BHRF1 gene or in introns contained within the viral BART transcripts. To understand the role of the BHRF1 miRNA cluster, we have constructed a virus mutant that lacks all its three members (D123) and a revertant virus. Here we show that the B cell transforming capacity of the D123 EBV mutant is reduced by more than 20-fold, relative to wild type or revertant viruses. B cells exposed to the knock-out virus displayed slower growth, and exhibited a two-fold reduction in the percentage of cells entering the cell cycle S phase. Furthermore, they displayed higher latent gene expression levels and latent protein production than their wild type counterparts. Therefore, the BHRF1 miRNAs accelerate B cell expansion at lower latent gene expression levels. Thus, this miRNA cluster simultaneous