A Viral microRNA Cluster Strongly Potentiates the Transforming Properties of a Human Herpesvirus

PLoS Pathogens

Bryan R. Cullen¹  Sarah D. Linnstaedt¹  Henri-Jacques Delecluse²  Regina Feederle²  Maja Bencun²  Helmut Bannert²  Helge Lips² 

[1] Center for Virology and Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, United States of America;Department of Virus Associated Tumours, German Cancer Research Center, Heidelberg, Germany

关键词: B cells;    MicroRNAs;    Epstein-Barr virus;    Polymerase chain reaction;    Cloning;    Gene expression;    Small nucleolar RNAs;    Viral gene expression;   

DOI  :  10.1371/journal.ppat.1001294

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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 (Δ123) and a revertant virus. Here we show that the B cell transforming capacity of the Δ123 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 simultaneously enhances expansion of the virus reservoir and reduces the viral antigenic load, two features that have the potential to facilitate persistence of the virus in the infected host. Thus, the EBV BHRF1 miRNAs may represent new therapeutic targets for the treatment of some EBV-associated lymphomas.

【 授权许可】

CC BY