Viruses can appropriate various host-cell pathways to increase their replicative and infective abilities. Now, a report published in Science reveals a novel mechanism by which hepatitis C virus (HCV) increases its abundance in the cell. Catherine Jopling and colleagues show that the HCV RNA genome binds to host-cell microRNA (miRNA) to facilitate viral replication.

miRNAs are small RNA molecules that regulate genes in many plant and animal species either by promoting mRNA cleavage or by preventing mRNA translation. Whereas many miRNAs are ubiquitously expressed, others are tissue specific. And in some instances, the expression of miRNAs is limited to certain cell lines — for example, liver-specific miR-122 is expressed in the Huh7 cell line, but not in HepG2 cells, both of which are derived from human hepatocytes. The Huh7 cell line can support HCV replication, and the authors asked whether this replicative ability could be related to the expression of miR-122 in this permissive cell line.

Inspection of the HCV genome revealed two potential miR-122 binding sites, one in the viral 3′ non-coding region (NCR) and the other in the viral 5′ NCR. To determine whether miR-122 regulates HCV gene expression, Jopling et al. studied the abundance of viral RNA in Huh7 cells that stably expressed an HCV replicon. When miR-122 was inactivated by sequestration using a complementary oligonucleotide, the amount of HCV replicon RNA was reduced by ∼80%. Similarly, replication-competent genomic HCV RNA accumulated in Huh7 cells only in the presence of miR-122.

By mutating the HCV genome and ectopically expressing miR-122 molecules with compensatory mutations, the authors showed that HCV RNA directly bound to miR-122 through the 5′ NCR, and that this interaction increased viral RNA levels.

Notably, although most miRNAs impinge on gene expression at the level of mRNA translation, this does not seem to be the case for miR-122. Experiments using replication-deficient HCV RNAs showed that mutations of the miR-122 binding site did not affect mRNA translation or stability. Instead, it seems that miR-122 positively influences viral replication, perhaps by aiding RNA folding or RNA accumulation into replication complexes.

This is the first example of an animal RNA that interacts with its target 5′ NCR, and it will be interesting to note whether other viral 5′ NCRs are similarly targeted by miRNAs. Finally, as a staggering 170 million people are currently infected with HCV, there is an urgent need for curative therapy. Based on these results, the authors hope that the targeted inactivation of miRNA-122 might prove to be effective antiviral therapy.