Kelly Elizabeth J, Hadac Elizabeth M, Greiner Suzanne, Russell Stephen J
Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Nat Med. 2008 Nov;14(11):1278-83. doi: 10.1038/nm.1776. Epub 2008 Oct 26.
The cellular tropisms of eukaryotic viruses are shaped by their need for entry receptors and intracellular transcription factors. Here we show that viral tropisms can also be regulated by tissue-specific microRNAs (miRNAs). Target sequences complementary to muscle-specific miRNAs were inserted into the 3' untranslated region (UTR) of an oncolytic picornavirus that causes lethal myositis in tumor-bearing mice. The recombinant virus still propagated in subcutaneous tumors, causing total regression and sustained viremia, but could not replicate in cells expressing complementary miRNAs and therefore did not cause myositis. This altered tropism was not due to insertional attenuation, as a control virus containing a 3' UTR insert with a disrupted miRNA target sequence fully retained its lethal myotropism. Tissue-specific destabilization of viral genomes by miRNA target insertion provides a potentially versatile new mechanism for controlling the tropism of replicating viruses for therapy and may serve as a new modality for attenuating viruses for vaccine purposes.
真核病毒的细胞嗜性由其对进入受体和细胞内转录因子的需求所塑造。在此我们表明，病毒嗜性也可受组织特异性微小RNA（miRNA）调控。将与肌肉特异性miRNA互补的靶序列插入到一种溶瘤微小核糖核酸病毒的3'非翻译区（UTR），该病毒可在荷瘤小鼠中引发致死性肌炎。重组病毒仍能在皮下肿瘤中增殖，导致肿瘤完全消退并持续病毒血症，但无法在表达互补miRNA的细胞中复制，因此不会引发肌炎。这种嗜性改变并非由于插入减弱，因为含有3'UTR插入片段且miRNA靶序列被破坏的对照病毒完全保留了其致死性肌嗜性。通过miRNA靶序列插入实现病毒基因组的组织特异性失稳，为控制复制病毒的嗜性用于治疗提供了一种潜在通用的新机制，并且可能作为一种用于疫苗目的使病毒减毒的新方式。
