miRNA independent hepacivirus variants suggest a strong evolutionary pressure to maintain miR-122 dependence
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
miRNA independent hepacivirus variants suggest a strong evolutionary pressure to maintain miR-122 dependence. / Yu, Yingpu; Scheel, Troels K.H.; Luna, Joseph M.; Chung, Hachung; Nishiuchi, Eiko; Scull, Margaret A.; Echeverría, Natalia; Ricardo-Lax, Inna; Kapoor, Amit; Lipkin, Ian W.; Divers, Thomas J.; Antczak, Douglas F.; Tennant, Bud C.; Rice, Charles M.
I: PLOS Pathogens, Bind 13, Nr. 10, e1006694, 2017.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - miRNA independent hepacivirus variants suggest a strong evolutionary pressure to maintain miR-122 dependence
AU - Yu, Yingpu
AU - Scheel, Troels K.H.
AU - Luna, Joseph M.
AU - Chung, Hachung
AU - Nishiuchi, Eiko
AU - Scull, Margaret A.
AU - Echeverría, Natalia
AU - Ricardo-Lax, Inna
AU - Kapoor, Amit
AU - Lipkin, Ian W.
AU - Divers, Thomas J.
AU - Antczak, Douglas F.
AU - Tennant, Bud C.
AU - Rice, Charles M.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
U2 - 10.1371/journal.ppat.1006694
DO - 10.1371/journal.ppat.1006694
M3 - Journal article
C2 - 29084265
AN - SCOPUS:85033234891
VL - 13
JO - P L o S Pathogens
JF - P L o S Pathogens
SN - 1553-7366
IS - 10
M1 - e1006694
ER -
ID: 185722260