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

Nat Commun. 2014 Nov 18;5:5408. doi: 10.1038/ncomms6408.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Hepacivirus / genetics*
  • Hepacivirus / physiology
  • Hepatitis C / genetics
  • Hepatitis C / metabolism*
  • Hepatitis C / virology
  • Humans
  • Liver / metabolism
  • Liver / virology
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Molecular Sequence Data
  • Point Mutation*
  • Virus Replication

Substances

  • MIRN122 microRNA, human
  • MicroRNAs

Associated data

  • SRA/SRR1588185