PLoS pathogens, 2017-10, Vol.13 (10), p.e1006694
2017
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- Autor(en) / Beteiligte
- Titel
- miRNA independent hepacivirus variants suggest a strong evolutionary pressure to maintain miR-122 dependence
- Ist Teil von
- PLoS pathogens, 2017-10, Vol.13 (10), p.e1006694
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2017
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Hepatitis C virus (HCV) requires the liver specific micro-RNA (miRNA), miR-122, to replicate. This was considered unique among RNA viruses until recent discoveries of HCV-related hepaciviruses prompting the question of a more general miR-122 dependence. Among hepaciviruses, the closest known HCV relative is the equine non-primate hepacivirus (NPHV). Here, we used Argonaute cross-linking immunoprecipitation (AGO-CLIP) to confirm AGO binding to the single predicted miR-122 site in the NPHV 5'UTR in vivo. To study miR-122 requirements in the absence of NPHV-permissive cell culture systems, we generated infectious NPHV/HCV chimeric viruses with the 5' end of NPHV replacing orthologous HCV sequences. These chimeras were viable even in cells lacking miR-122, although miR-122 presence enhanced virus production. No other miRNAs bound this region. By random mutagenesis, we isolated HCV variants partially dependent on miR-122 as well as robustly replicating NPHV/HCV variants completely independent of any miRNAs. These miRNA independent variants even replicate and produce infectious particles in non-hepatic cells after exogenous delivery of apolipoprotein E (ApoE). Our findings suggest that miR-122 independent HCV and NPHV variants have arisen and been sampled during evolution, yet miR-122 dependence has prevailed. We propose that hepaciviruses may use this mechanism to guarantee liver tropism and exploit the tolerogenic liver environment to avoid clearance and promote chronicity.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1553-7374, 1553-7366eISSN: 1553-7374DOI: 10.1371/journal.ppat.1006694Titel-ID: cdi_plos_journals_1965107466
- Format
- –
- Schlagworte
- Apolipoprotein E, Apolipoproteins, Apolipoproteins E - genetics, Apolipoproteins E - metabolism, Argonaute Proteins - genetics, Argonaute Proteins - metabolism, Binding sites, Biology and life sciences, Cell culture, Cell Line, Tumor, Chimeras, Crosslinking, Eukaryotic Initiation Factors - genetics, Eukaryotic Initiation Factors - metabolism, Evolution, Molecular, Genetic aspects, Hepacivirus - genetics, Hepacivirus - metabolism, Hepatitis, Hepatitis C, Hepatitis C - genetics, Hepatitis C - metabolism, Hepatitis C virus, Humans, Immunology, Immunoprecipitation, In vivo methods and tests, Infectious diseases, Interferon, Laboratories, Liver, Medicine and Health Sciences, MicroRNA, MicroRNAs, MicroRNAs - genetics, MicroRNAs - metabolism, miRNA, Mutagenesis, Random mutagenesis, Replication, Research and Analysis Methods, Ribonucleic acid, RNA, RNA viruses, Software, Tropism, Veterinary colleges, Veterinary medicine, Viral Tropism - physiology, Virology, Viruses