Hepatitis C virus and interferon type III (interferon-λ3/interleukin-28B and interferon-λ4): genetic basis of susceptibility to infection and response to antiviral treatment.

There has been a significant increase in our understanding of the host genetic determinants of susceptibility to viral infections in recent years. Recently, two single-nucleotide polymorphisms (SNPs), rs12979860 T/C and rs8099917 T/G, upstream of the interleukin (IL)-28B/interferon (IFN)-λ3 gene have been clearly associated with spontaneous and treatment-induced viral clearance in hepatitis C virus (HCV) infection. Because of their power in predicting the response to IFN/ribavirin therapy, the above SNPs have been used as a diagnostic tool, even though their relevance in the management of HCV infection will be blunt in the era of IFN-free regimens. The recent discovery of a new genetic variant, ss469415590 TT/ΔG, upstream of the IL-28B gene, which generates the novel IFN-λ4 protein, has opened up a new and alternative scenario to understand the functional architecture of type III IFN genomic regions and to improve our knowledge of the pathogenetic mechanism of HCV infection. A role of ss469415590 in predicting responsiveness to antiviral therapy has also been observed in HCV-infected patients receiving direct antiviral agents. The underlying biological mechanism that links the above IL-28B polymorphisms (in both IFN-λ3 and IFN-λ4) to spontaneous and treatment-induced clearance of HCV infection remains to be discovered. Despite this, shedding some light on this issue, which is the main aim of this review, may provide new insights into the general topic of 'host genetics and viral infections'.