A Human Torque Teno Virus Encodes a MicroRNA That Inhibits Interferon Signaling

PLoS Pathogens

Ethel-Michele de Villiers¹  Christopher S. Sullivan²  Rodney P. Kincaid²  Jennifer C. Cox²  James M. Burke² 

[1] Division for the Characterization of Tumorviruses, Deutsches Krebsforschungszentrum, Heidelberg, Germany;The University of Texas at Austin, Molecular Genetics & Microbiology, Austin, Texas, United States of America

关键词: MicroRNAs;    Small interfering RNAs;    Interferons;    RNA sequencing;    Viral replication;    RNA sequence analysis;    Northern blot;    Transfection;   

DOI  :  10.1371/journal.ppat.1003818

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Torque teno viruses (TTVs) are a group of viruses with small, circular DNA genomes. Members of this family are thought to ubiquitously infect humans, although causal disease associations are currently lacking. At present, there is no understanding of how infection with this diverse group of viruses is so prevalent. Using a combined computational and synthetic approach, we predict and identify miRNA-coding regions in diverse human TTVs and provide evidence for TTV miRNA production in vivo. The TTV miRNAs are transcribed by RNA polymerase II, processed by Drosha and Dicer, and are active in RISC. A TTV mutant defective for miRNA production replicates as well as wild type virus genome; demonstrating that the TTV miRNA is dispensable for genome replication in a cell culture model. We demonstrate that a recombinant TTV genome is capable of expressing an exogenous miRNA, indicating the potential utility of TTV as a small RNA vector. Gene expression profiling of host cells identifies N-myc (and STAT) interactor (NMI) as a target of a TTV miRNA. NMI transcripts are directly regulated through a binding site in the 3′UTR. SiRNA knockdown of NMI contributes to a decreased response to interferon signaling. Consistent with this, we show that a TTV miRNA mediates a decreased response to IFN and increased cellular proliferation in the presence of IFN. Thus, we add Annelloviridae to the growing list of virus families that encode miRNAs, and suggest that miRNA-mediated immune evasion can contribute to the pervasiveness associated with some of these viruses.

【 授权许可】

CC BY