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一种通过延长识别结构域增强HIV-1 RNA剪接的U1i RNA是HIV-1联合基因治疗的最佳候选物。

A U1i RNA that Enhances HIV-1 RNA Splicing with an Elongated Recognition Domain Is an Optimal Candidate for Combination HIV-1 Gene Therapy.

作者信息

Del Corpo Olivier, Goguen Ryan P, Malard Camille M G, Daher Aïcha, Colby-Germinario Susan, Scarborough Robert J, Gatignol Anne

机构信息

Lady Davis Institute for Medical Research, Montréal, QC H3T 1E2, Canada; Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, QC H3A 0G4, Canada.

Lady Davis Institute for Medical Research, Montréal, QC H3T 1E2, Canada; Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 0G4, Canada.

出版信息

Mol Ther Nucleic Acids. 2019 Dec 6;18:815-830. doi: 10.1016/j.omtn.2019.10.011. Epub 2019 Oct 18.

DOI:10.1016/j.omtn.2019.10.011
PMID:31734561
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6861678/
Abstract

U1 interference (U1i) RNAs can be designed to correct splicing defects and target pathogenic RNA, such as HIV-1 RNA. In this study, we show that U1i RNAs that enhance HIV-1 RNA splicing are more effective at inhibiting HIV-1 production compared to top U1i RNAs that inhibit polyadenylation of HIV-1 RNA. A U1i RNA was also identified targeting a site upstream of the first splice acceptor site in the Gag coding region that was effective at inhibiting HIV-1 production. U1-T6, which enhanced HIV-1 RNA splicing, was superior to an antiviral short hairpin RNA (shRNA) currently in clinical trials. To increase specificity, the recognition domain of U1-T6 was elongated by 3-6 nt. The elongated molecules inhibited HIV-1 production from different HIV-1 strains, including one with a mismatch in the target site. These results suggest that lengthening the recognition domain can enhance the specificity of U1i RNAs for their intended target sites while at the same time allowing them to tolerate single mismatch mutations. Overall, our results demonstrate that U1-T6 with an elongated recognition domain inhibits HIV-1 production and has both the efficacy and specificity to be a promising candidate for HIV-1 gene therapy.

摘要

U1干扰（U1i）RNA可被设计用于纠正剪接缺陷并靶向致病RNA，如HIV-1 RNA。在本研究中，我们发现，与抑制HIV-1 RNA多聚腺苷酸化的顶级U1i RNA相比，增强HIV-1 RNA剪接的U1i RNA在抑制HIV-1产生方面更有效。还鉴定出一种U1i RNA靶向Gag编码区第一个剪接受体位点上游的一个位点，该位点在抑制HIV-1产生方面有效。增强HIV-1 RNA剪接的U1-T6优于目前正在进行临床试验的一种抗病毒短发夹RNA（shRNA）。为了提高特异性，将U1-T6的识别结构域延长了3至6个核苷酸。延长后的分子抑制了不同HIV-1毒株的HIV-1产生，包括一种在靶位点存在错配的毒株。这些结果表明，延长识别结构域可以增强U1i RNA对其预期靶位点的特异性，同时使它们能够耐受单个错配突变。总体而言，我们的结果表明，具有延长识别结构域的U1-T6抑制HIV-1产生，并且具有作为HIV-1基因治疗有前景候选物的效力和特异性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ca/6861678/e1a91e7dc855/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ca/6861678/7780c6353fa9/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ca/6861678/d14075f27094/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ca/6861678/981f236c6616/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ca/6861678/557a99494598/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ca/6861678/80a95775cf4d/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ca/6861678/253a94ba96ad/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ca/6861678/e1a91e7dc855/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ca/6861678/7780c6353fa9/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ca/6861678/d14075f27094/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ca/6861678/981f236c6616/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ca/6861678/557a99494598/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ca/6861678/80a95775cf4d/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ca/6861678/253a94ba96ad/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44ca/6861678/e1a91e7dc855/gr7.jpg

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