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

Autor: Israelow B; Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA., Mullokandov G; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA., Agudo J; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA., Sourisseau M; Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA., Bashir A; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA., Maldonado AY; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA., Dar AC; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA., Brown BD; 1] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA [2] Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA [3] Diabetes, Metabolism and Obesity Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA [4] Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA., Evans MJ; Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2014 Nov 18; Vol. 5, pp. 5408. Date of Electronic Publication: 2014 Nov 18.
DOI: 10.1038/ncomms6408
Abstrakt: 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.
Databáze: MEDLINE
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