In a recent article (25 years of interferon-based treatment of chronic hepatitis C: an epoch coming to an end. Nature Rev. Immunol. 13, 535–542 (2013))1, Markus Heim reviewed the 25-year history of therapies for hepatitis C virus (HCV) infection and introduced some new pharmaceutical agents that target cellular proteins and the microRNA miR-122. The author also described an association between a polymorphism in interleukin-28B (IL28B; also known as IFNL3) and the response to interferon-α (IFNα) treatment, but he did not review the molecular mechanisms that link genetic variation in the IL28B gene locus to the response to IFNα1. We would like to highlight a possible link between miR-122, the IL28B gene polymorphism and the response to IFNα treatment.
Janssen et al.2 recently reported a Phase IIa clinical study of miR-122-targeted therapy (miravirsen), which showed that the use of miravirsen in patients with chronic HCV genotype 1 infection leads to a prolonged dose-dependent reduction in HCV RNA levels and no signs of viral resistance. miR-122 is a highly abundant microRNA that is expressed in the liver and is essential for the stability and propagation of HCV RNA3. Recently, a report has shown that pretreatment levels of miR-122 are predictive of the response to IFN and that miR-122 levels might be related to the IL28B genotype4. Su et al.4 reported that serum levels of miR-122 can be used as a surrogate marker of hepatic levels of miR-122 and that serum levels of miR-122 positively correlated with hepatic necroinflammation. Patients who showed a complete early and sustained response to treatment had significantly higher serum levels of miR-122 before treatment compared with patients who had no response; in particular, a strong response to treatment was shown by patients who were infected with HCV genotype 2 and had the IL28B rs8099917 TT genotype. Su et al.4 also showed that patients with the IL28B TT genotype had significantly better treatment responses and higher serum levels of miR-122 before treatment compared with those with the IL28B GT or GG genotypes4.
Therefore, the IL28B genotype-dependent variation in levels of miR-122 in serum could be one of the molecular mechanisms that links genotype to the response to IFNα5. This might be through a recently discovered mechanism by which IFNα-induced cytosolic 5′ nucleotidase 3 (NT5C3) mRNA reduces miR-122 levels by sequestration, a process that is reversible by transduction with small interfering RNA that targets NT5C3. This mechanism links genotypes associated with an activated endogenous IFN system to a poor response to IFNα treatment6. Furthermore, the IL28B TT genotype is associated with the upregulation of expression of the IFNα receptor α-chain, and it is possible that the increased action of endogenous IFNα might also enhance the degradation of the anti-HCV microRNA let-7b through the same NT5C3 mRNA-dependent mechanism. This reduction in let-7b levels could compromise the action of exogenous IFNα, which is known to act synergistically with let-7b7. Therefore, in this context, it is possible that miR-122 levels are just a correlate of let-7b levels and that the regulation of let7b, and not miR-122, determines the response to exogenous IFNα. Because miR-122 acts as a tumour suppressor for hepatocellular carcinoma8, attention needs to be paid to the long-term outcome of treatment with suppressors of miR-122.
References
Heim, M. H. 25 years of interferon-based treatment of chronic hepatitis C: an epoch coming to an end. Nature Rev. Immunol. 13, 535–542 (2013).
Janssen, H. L. et al. Treatment of HCV infection by targeting microRNA. N. Engl. J. Med. 368, 1685–1694 (2013).
Henke, J. I. et al. MicroRNA-122 stimulates translation of hepatitis C virus RNA. EMBO. J. 27, 3300–3310 (2008).
Su, T. H. et al. Serum microRNA-122 level correlates with virologic responses to pegylated interferon therapy in chronic hepatitis C. Proc. Natl Acad. Sci. USA 110, 7844–7849 (2013).
Hayesl, C. N., Imamura, M., Aikata, H. & Chayama, K. Genetics of IL28B and HCV—response to infection and treatment. Nature Rev. Gastroenterol. Hepatol. 9, 406–417 (2012).
Hao, J. et al. Inhibition of alpha interferon (IFN-α)-induced microRNA-122 negatively affects the anti-hepatitis B virus efficiency of IFN-α. J. Virol. 87, 137–147 (2013).
Cheng, J. C. et al. Let-7b is a novel regulator of hepatitis C virus replication. Cell. Mol. Life Sci. 69, 2621–2633 (2012).
Tsai, W. C. et al. MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma. Hepatology 49, 1571–1582 (2009).
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Shin, J., Eisenhut, M. miR-122, IL28B genotype and the response to interferon in chronic hepatitis C virus infection. Nat Rev Immunol 13, 902 (2013). https://doi.org/10.1038/nri3463-c1
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DOI: https://doi.org/10.1038/nri3463-c1
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