Hepatitis C virus genetics affects miR-122 requirements and response to miR-122 inhibitors.
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.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA.
Benjamin
B
Israelow
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.
Gavriel
G
Mullokandov
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.
Judith
J
Agudo
Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA.
Marion
M
Sourisseau
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.
Ali
A
Bashir
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA.
Andres Y
AY
Maldonado
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA.
Arvin C
AC
Dar
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.
Brian D
BD
Brown
Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, New York 10029, USA.
Matthew J
MJ
Evans
D001483:Base Sequence; D016174:Hepacivirus / Q000235:genetics* / Q000502:physiology; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000821:virology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D017354:Point Mutation; D014779:Virus Replication
C531907:MIRN122 microRNA, human; D035683:MicroRNAs