In particular, we will focus on the newly defined role of cellular microRNA (miR-122) in viral replication and discuss its potential for HCV molecular therapy.
The liver-specific miR-122, however, exerts a positive effect on HCV (hepatitis C virus) RNA levels by binding directly to a site in the 5'-UTR of the viral RNA.
The liver-specific microRNA-122 (miR-122) contributes to the liver tropism of Hepatitis C Virus (HCV) by accelerating the binding of ribosomes to the viral RNA and thereby stimulating HCV translation.
An inhibitor of microRNA-122 reduces viral load in chimpanzees that are chronically infected with hepatitis C virus, suggesting that such an approach might have therapeutic potential in humans.
In higher eukaryotes, the tightly controlled expression of different miRNAs, each of which regulates multiple target mRNAs, is crucial for the maintenance of tissue type and the control of differentiation. miR-122 is a highly liver-specific miRNA that is important in hepatitis C virus infection, cholesterol metabolism and hepatocellular carcinoma.
We found that miR-21 expression correlated with viral load, fibrosis and serum liver transaminase levels. miR-122 expression inversely correlated with fibrosis, liver transaminase levels and patient age. miR-21 was induced ∼twofold, and miR-122 was downregulated on infection of cultured cells with the HCV J6/JFH infectious clone, thus establishing a link to HCV.
Whereas miR-21 extracellular levels were unchanged, extracellular levels of miR-122, miR-34a and to a lesser extent miR-16, steadily increased during the course of HCV infection, independently of viral replication and production.
Hybridization between the host-encoded, liver-specific microRNA (miR-122) and the 5'-untranslated region of HCV genome was shown to be required for effective viral RNA replication.
Furthermore, hepatic miR-122 expression in patients seronegative for HCV RNA was significantly higher than that in patients seropositive for HCV RNA (P<0.0001).
We also make an argument that current proposed therapy with hsa-miR-122 may not be the optimal choice for HCV patients since it lacks essential gene alignment and may be harmful for the patients.
In conclusion, although miR-122 facilitates efficient viral replication in nonhepatic cells, factors other than miR-122, which are most likely specific to hepatocytes, are required for HCV assembly.
Here we will review recent advances in the relationship between HCV infection and miRNAs, showing that some of them emerge in publications as challengers against the supremacy of miR-122.
This review summarizes the success of sequestration of liver-specific microRNA miR-122 by antisense locked nucleic acids and their use in combating hepatitis C virus in clinical trials.
The interaction of HCV with the highly liver-enriched miRNA, miR-122 represents one such unique example of viruses having evolved mechanism(s) to usurp the host miRNA machinery to support viral life cycle.
Taken together, our data, along with the fact that antisense oligonucleotides of miR122 also directly inhibit HCV replication, suggest that a combination therapy comprising IFN and silencing of miR122 function may be a promising therapeutic option in the near future.
However, the levels of Ago2 protein do not substantially change during cell cycle phases, indicating that other cellular factors involved in HCV translation stimulation by miR-122 may be differentially expressed in different cell cycle phases.
Notably, a clinical trial targeting miR-122 with the anti-miR-122 oligonucleotides miravirsen, the first miRNA targeted drug, has been initiated for treatment of HCV infection.
These findings reveal critical functions for miR-122 in the maintenance of liver homeostasis and have important therapeutic implications, including the potential utility of miR-122 delivery for selected patients with HCC and the need for careful monitoring of patients receiving miR-122 inhibition therapy for HCV.
As a result, we have developed a high-throughput screen for potential small-molecule regulators of the liver-specific microRNA miR-122, which is involved in hepatocellular carcinoma development and hepatitis C virus infection.