Modulation of Hepatitis C Virus RNA Abundance by a Liver-Specific MicroRNA

TLDR

MicroRNAs regulate mRNA expression, and the liver‑specific miR‑122 is highly abundant in human liver. Mutational analysis of the viral 5′ noncoding region and compensatory miR‑122 mutants revealed a direct genetic interaction between miR‑122 and the HCV genome. Sequestration of miR‑122 in liver cells markedly reduces autonomously replicating HCV RNAs, indicating that miR‑122 facilitates viral RNA replication and represents a potential antiviral target.

Abstract

MicroRNAs are small RNA molecules that regulate messenger RNA (mRNA) expression. MicroRNA 122 (miR-122) is specifically expressed and highly abundant in the human liver. We show that the sequestration of miR-122 in liver cells results in marked loss of autonomously replicating hepatitis C viral RNAs. A genetic interaction between miR-122 and the 5′ noncoding region of the viral genome was revealed by mutational analyses of the predicted microRNA binding site and ectopic expression of miR-122 molecules containing compensatory mutations. Studies with replication-defective RNAs suggested that miR-122 did not detectably affect mRNA translation or RNA stability. Therefore, miR-122 is likely to facilitate replication of the viral RNA, suggesting that miR-122 may present a target for antiviral intervention.