Título:
miRNA independent hepacivirus variants suggest a strong evolutionary pressure to maintain miR-122 dependence
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Autor:
Yu, Y.
Scheel, T. K. H.
Luna, J. M.
Chung, H.
Nishiuchi, E.
Scull, M. A.
Echeverría Chagas, Natalia
Ricardo-Lax, I.
Kapoor, A.
Lipkin, I. W.
Divers, T. J.
Antczak, D. F.
Tennant, B. C.
Rice, C. M.
Scheel, T. K. H.
Luna, J. M.
Chung, H.
Nishiuchi, E.
Scull, M. A.
Echeverría Chagas, Natalia
Ricardo-Lax, I.
Kapoor, A.
Lipkin, I. W.
Divers, T. J.
Antczak, D. F.
Tennant, B. C.
Rice, C. M.
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Tipo de documento:
Artículo
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Palabras clave:
MicroRNAs
Carcinoma Hepatocellular
HCC tissues
Carcinoma Hepatocellular
HCC tissues
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Año de publicación:
2017
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Resumen:
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.
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PLoS
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PLoS Pathogens, 2017, 13 (10), art. no. e1006694
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Citación:
Yu, Y., Scheel, T., Luna J., y otros. "miRNA independent hepacivirus variants suggest a strong evolutionary pressure to maintain miR-122 dependence". PLoS Pathogens [en línea], 2017, 13 (10), art. no. e1006694. doi: 10.1371/journal.ppat.1006694
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1553-7366
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Licencia Creative Commons Atribución (CC - By 4.0)
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| Ficheros | Descripción | Tamaño | Formato | ||
|---|---|---|---|---|---|
| 101371journalppat1006694.pdf | — | 3.95 MB | Adobe PDF |