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

Benjamin Israelow, Gavriel Mullokandov, Judith Agudo, Marion Sourisseau, Ali Bashir, Andres Y. Maldonado, Arvin C. Dar, Brian D. Brown () and Matthew J. Evans ()
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Benjamin Israelow: Icahn School of Medicine at Mount Sinai
Gavriel Mullokandov: Icahn School of Medicine at Mount Sinai
Judith Agudo: Icahn School of Medicine at Mount Sinai
Marion Sourisseau: Icahn School of Medicine at Mount Sinai
Ali Bashir: Icahn School of Medicine at Mount Sinai
Andres Y. Maldonado: Icahn School of Medicine at Mount Sinai
Arvin C. Dar: Icahn School of Medicine at Mount Sinai
Brian D. Brown: Icahn School of Medicine at Mount Sinai
Matthew J. Evans: Icahn School of Medicine at Mount Sinai

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6408

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