TY - JOUR
T1 - Hepatitis C virus genetics affects miR-122 requirements and response to miR-122 inhibitors
AU - Israelow, Benjamin
AU - Mullokandov, Gavriel
AU - Agudo, Judith
AU - Sourisseau, Marion
AU - Bashir, Ali
AU - Maldonado, Andres Y.
AU - Dar, Arvin C.
AU - Brown, Brian D.
AU - Evans, Matthew J.
N1 - Funding Information:
We are grateful to Charles Rice for HCV-related plasmids, and Timothy Tellinghuisen and Charles Rice for the 9E10 anti-HCV NS5A antibody. This work was supported by the US National Institutes of Health (R01DK095125, R00AI077800 and R56AI091792 to M.J.E., R01AI104848 and R33CA182377 to B.D.B, F30DK096892 to B.I. and F30HL119039 to G.M.), a USPHS Institutional Research Training Award (AI07647 to B.I.), an American Cancer Society Research Scholar Grant (RSG-12-176-01-MPC to M.J.E.), the Pew Charitable Funds (M.J.E.) and Human Frontiers Science Program Award RGP0009/2014 (B.D.B).
Publisher Copyright:
© 2014 Macmillan Publishers Limited. All rights reserved.
PY - 2015/2
Y1 - 2015/2
N2 - Hepatitis C virus (HCV) replication is dependent on a liver-specific microRNA (miRNA), miR-122. A recent clinical trial reported that transient inhibition of miR-122 reduced viral titres in HCV-infected patients. Here we set out to better understand how miR-122 inhibition influences HCV replication over time. Unexpectedly, we observed the emergence of an HCV variant that is resistant to miR-122 knockdown. Next-generation sequencing revealed that this was due to a single nucleotide change at position 28 (G28A) of the HCV genome, which falls between the two miR-122 seed-binding sites. Naturally occurring HCV isolates encoding G28A are similarly resistant to miR-122 inhibition, indicating that subtle differences in viral sequence, even outside the seed-binding site, greatly influence HCV's miR-122 concentration requirement. In addition, we found that HCV itself reduces miR-122's activity in the cell, possibly through binding and sequestering miR-122. Our study provides insight into the interaction between miR-122 and HCV, including viral adaptation to reduced miR-122 bioavailability, and has implications for the development of anti-miR-122-based HCV drugs.
AB - Hepatitis C virus (HCV) replication is dependent on a liver-specific microRNA (miRNA), miR-122. A recent clinical trial reported that transient inhibition of miR-122 reduced viral titres in HCV-infected patients. Here we set out to better understand how miR-122 inhibition influences HCV replication over time. Unexpectedly, we observed the emergence of an HCV variant that is resistant to miR-122 knockdown. Next-generation sequencing revealed that this was due to a single nucleotide change at position 28 (G28A) of the HCV genome, which falls between the two miR-122 seed-binding sites. Naturally occurring HCV isolates encoding G28A are similarly resistant to miR-122 inhibition, indicating that subtle differences in viral sequence, even outside the seed-binding site, greatly influence HCV's miR-122 concentration requirement. In addition, we found that HCV itself reduces miR-122's activity in the cell, possibly through binding and sequestering miR-122. Our study provides insight into the interaction between miR-122 and HCV, including viral adaptation to reduced miR-122 bioavailability, and has implications for the development of anti-miR-122-based HCV drugs.
UR - http://www.scopus.com/inward/record.url?scp=84923303850&partnerID=8YFLogxK
U2 - 10.1038/ncomms6408
DO - 10.1038/ncomms6408
M3 - Article
C2 - 25403145
AN - SCOPUS:84923303850
SN - 2041-1723
VL - 5
JO - Nature Communications
JF - Nature Communications
M1 - 5408
ER -