In their response to my Review 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, Jae Il Shin and Michael Eisenhut (miR-122, IL28B genotype and the response to interferon in chronic hepatitis C virus infection. Nature Rev. Immunol. (2013))2 highlight a possible link between the microRNA miR-122, the interleukin-28B (IL28B; also known as IFNL3) genotype and the response to interferon-α (IFNα) treatment in patients with chronic hepatitis C virus infection.
Indeed, we previously reported the association between miR-122 expression and the response to treatment3, which was recently confirmed by Su et al.4. Patients with normal miR-122 expression levels are significantly more likely to have a sustained virological response to treatment with pegylated IFNα and ribavirin, whereas low miR-122 expression levels are associated with no virological response3. As described in detail in the recent Review article1, several groups have reported that patients with induced expression of IFN-stimulated genes (ISGs) in the liver, as measured in pretreatment biopsy samples, are poor responders to pegylated IFNα and ribavirin5,6,7. The link between high ISG expression and low miR-122 expression has been elusive, but the recent paper by Hao et al.8 showing that miR-122 could be sequestered by binding to the 3′ untranslated region of the mRNA encoding cytosolic 5′ nucleotidase 3 (NT5C3), a classical ISG, indeed provides a potential explanation that should be explored more quantitatively in human liver biopsy samples.
Also, several groups have reported a significant association between the IL28B genotype and the expression of ISGs in liver biopsy samples taken before treatment9,10,11. However, the molecular mechanisms that are responsible for ISG induction in patients with minor alleles of the IL28B gene locus are unknown.
Taken together, the significant associations between IL28B genotype, hepatic ISG expression and hepatic miR-122 expression are now firmly established. However, the molecular mechanisms underlying these statistical associations remain to be uncovered, and they continue to be a central question and formidable challenge in this research field.
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).
Shin, J. I. & Eisenhut, M. miR-122, IL28B genotype and the response to interferon in chronic hepatitis C virus infection. Nature Rev. Immunol. http://dx.doi.org/nri3463-c1 (2013).
Sarasin-Filipowicz, M., Krol, J., Markiewicz, I., Heim, M. H. & Filipowicz, W. Decreased levels of microRNA miR-122 in individuals with hepatitis C responding poorly to interferon therapy. Nature Med. 15, 31–33 (2009).
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).
Sarasin-Filipowicz, M. et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc. Natl Acad. Sci. USA 105, 7034–7039 (2008).
Chen, L. et al. Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection. Gastroenterology 128, 1437–1444 (2005).
Asselah, T. et al. Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C. Gut 57, 516–524 (2008).
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).
Urban, T. J. et al. IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C. Hepatology 52, 1888–1896 (2010).
Honda, M. et al. Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C. Gastroenterology 139, 499–509 (2010).
Dill, M. T. et al. Interferon-induced gene expression is a stronger predictor of treatment response than IL28B genotype in patients with hepatitis C. Gastroenterology 140, 1021–1031 (2011).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no competing financial interests.
Rights and permissions
About this article
Cite this article
Heim, M. Reply to 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-c2
Published:
Issue Date:
DOI: https://doi.org/10.1038/nri3463-c2
