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

• Published in: Nature communications 2014-11, Vol.5 (1), p.5408-5408, Article 5408
• Main Authors: Israelow, Benjamin, Mullokandov, Gavriel, Agudo, Judith, Sourisseau, Marion, Bashir, Ali, Maldonado, Andres Y., Dar, Arvin C., Brown, Brian D., Evans, Matthew J.
• Format: Article
• Language: English
• Subjects: 631/326/596/1905; 631/326/596/2555; 631/337/384/331; 631/92/436; Base Sequence; Binding sites; Bioavailability; Clinical trials; Drug dosages; Drug resistance; Genomes; Hepacivirus; Hepacivirus - genetics; Hepacivirus - physiology; Hepatitis C; Hepatitis C - genetics; Hepatitis C - metabolism; Hepatitis C - virology; Humanities and Social Sciences; Humans; Infections; Life Sciences; Liver; Liver - metabolism; Liver - virology; Medicine; Microbiology and Parasitology; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Molecular Sequence Data; multidisciplinary; Point Mutation; Science; Science (multidisciplinary); Virology; Virus Replication; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms6408

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. Replication of the hepatitis C virus (HCV) requires a host RNA molecule, miR-122, whose transient inhibition is being explored as an antiviral therapy. Here, the authors study the interaction between miR-122 and HCV, and identify mutations in HCV strains that affect susceptibility to miR-122 inhibition.