Journal
PLOS PATHOGENS
Volume 13, Issue 10, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1006694
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Categories
Funding
- Agriculture and Food Research initiative Competitive Grant from the USDA National institute of Food and Agriculture, NIH, NIAID [2016-67015-24765, AI116943]
- Danish Council for Independent Research [0602-02148, 6110-00595, 6111-00314]
- Novo Nordisk Foundation [NNF150C0017404]
- Lundbeck Foundation [R192-2015-1154]
- Weimann Foundation
- Lundbeck Foundation [R192-2015-1154] Funding Source: researchfish
- Novo Nordisk Fonden [NNF15OC0017404, NNF14OC0012533] Funding Source: researchfish
- NIFA [810811, 2016-67015-24765] Funding Source: Federal RePORTER
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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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