miR-122-based therapies select for three distinct resistance mechanisms based on alterations in RNA structure.
| Autor: | Chahal J; Department of Microbiology & Immunology, McGill University, Montréal, QC H3G 1Y6, Canada., Gebert LFR; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037., Camargo C; Department of Microbiology & Immunology, McGill University, Montréal, QC H3G 1Y6, Canada., MacRae IJ; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037., Sagan SM; Department of Microbiology & Immunology, McGill University, Montréal, QC H3G 1Y6, Canada; selena.sagan@mcgill.ca.; Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada. |
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| Jazyk: | angličtina |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Aug 17; Vol. 118 (33). |
| DOI: | 10.1073/pnas.2103671118 |
| Abstrakt: | Hepatitis C virus (HCV) is a positive-sense RNA virus that interacts with a liver-specific microRNA called miR-122. miR-122 binds to two sites in the 5' untranslated region of the viral genome and promotes HCV RNA accumulation. This interaction is important for viral RNA accumulation in cell culture, and miR-122 inhibitors have been shown to be effective at reducing viral titers in chronic HCV-infected patients. Herein, we analyzed resistance-associated variants that were isolated in cell culture or from patients who underwent miR-122 inhibitor-based therapy and discovered three distinct resistance mechanisms all based on changes to the structure of the viral RNA. Specifically, resistance-associated variants promoted riboswitch activity, genome stability, or positive-strand viral RNA synthesis, all in the absence of miR-122. Taken together, these findings provide insight into the mechanism(s) of miR-122-mediated viral RNA accumulation and provide mechanisms of antiviral resistance mediated by changes in RNA structure. Competing Interests: The authors declare no competing interest. (Copyright © 2021 the Author(s). Published by PNAS.) |
| Databáze: | MEDLINE |
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