期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 20, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/ijms20051088
关键词
antisense oligonucleotides; locked nucleic acids; splicing regulatory elements; mRNA degradation; human immunodeficiency virus type 1 (HIV-1)
资金
- Deutsche Forschungsgemeinschaft (DFG) [SCHA909/8-1]
- Forschungskommission of the Heinrich-Heine-University, Dusseldorf
- Heinz-Ansmann Stiftung fur AIDS-Forschung, Dusseldorf
- Jurgen Manchot Stiftung
Transcription of the HIV-1 provirus generates a viral pre-mRNA, which is alternatively spliced into more than 50 HIV-1 mRNAs encoding all viral proteins. Regulation of viral alternative splice site usage includes the presence of splicing regulatory elements (SREs) which can dramatically impact RNA expression and HIV-1 replication when mutated. Recently, we were able to show that two viral SREs, G(I3)-2 and ESEtat, are important players in the generation of viral vif, vpr and tat mRNAs. Furthermore, we demonstrated that masking these SREs by transfected locked nucleic acid (LNA) mixmers affect the viral splicing pattern and viral particle production. With regard to the development of future therapeutic LNA mixmer-based antiretroviral approaches, we delivered the G(I3)-2 and the ESEtat LNA mixmers nakedly, without the use of transfection reagents (gymnosis) into HIV-1 infected cells. Surprisingly, we observed that gymnotically-delivered LNA mixmers accumulated in the cytoplasm, and seemed to co-localize with GW bodies and induced degradation of mRNAs containing their LNA target sequence. The G(I3)-2 and the ESEtat LNA-mediated RNA degradation resulted in abrogation of viral replication in HIV-1 infected Jurkat and PM1 cells as well as in PBMCs.
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