Unknown

Dataset Information

0

Hepatitis C virus genetics affects miR-122 requirements and response to miR-122 inhibitors.


ABSTRACT: 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.

SUBMITTER: Israelow B 

PROVIDER: S-EPMC4236719 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

altmetric image

Publications

Hepatitis C virus genetics affects miR-122 requirements and response to miR-122 inhibitors.

Israelow Benjamin B   Mullokandov Gavriel G   Agudo Judith J   Sourisseau Marion M   Bashir Ali A   Maldonado Andres Y AY   Dar Arvin C AC   Brown Brian D BD   Evans Matthew J MJ  

Nature communications 20141118


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 posi  ...[more]

Similar Datasets

2015-01-06 | GSE64680 | GEO
2015-01-06 | GSE64679 | GEO
| S-EPMC4381172 | biostudies-literature
| S-EPMC4386883 | biostudies-literature
2015-01-06 | E-GEOD-64680 | biostudies-arrayexpress
2015-01-06 | E-GEOD-64679 | biostudies-arrayexpress
2015-01-06 | GSE64677 | GEO
2015-01-06 | E-GEOD-64677 | biostudies-arrayexpress
| S-EPMC3271899 | biostudies-other
| S-EPMC9907111 | biostudies-literature