Background:  Around 30% of individuals infected with the hepatitis C virus (HCV) spontaneously resolve the infection. Of those progressing to chronic hepatitis C, interferon-based therapy leads to permanent recovery from HCV infection in some 40% of cases. The divergent outcomes despite similar exposure to HCV and identical treatment regimens strongly point to genetic determinants for the natural and treatment-induced control of HCV infection. Candidate gene studies identified polymorphisms in human leukocyte antigens, killer immunoglobulin-like receptors, chemokines, interleukins, and interferon-stimulated genes that influence the control of HCV infection. Last year, several groups independently screened the entire human genome for common genetic variation associated with spontaneous or treatment-induced recovery from HCV infection. These genome-wide association studies (GWAS) consistently identified genetic variation in interleukin 28B (IL28B) as the strongest predictor for the control of HCV infection. Importantly, genetic variation in IL28B strongly predicted both spontaneous and treatment-induced HCV recovery, with a similar effect in HCV mono-infected and HCV/HIV co-infected individuals. IL28B on chromosome 19 encodes interferon-l, a type III interferon with antiviral activity mediated through the JAK-STAT pathway by inducing interferon-stimulated genes. The single nucleotide polymorphisms (SNP) identified in the GWAS are in high linkage disequilibrium with coding or functional non-coding SNP that might modulate function or expression of IL28B. The first links to causality were lower IL28B expression levels in individuals carrying the risk alleles, and haplotypes containing coding and promoter SNP associated with persistent HCV infection.

Conclusions:  Future studies should reveal the role of the different alleles on gene expression and cytokine production. The association of IL28B with natural and treatment-induced control of HCV underscores the role of innate immunity and of interferon-l for the control of HCV and has several implications for the understanding and management of HCV infection:  First, information on IL28B polymorphisms could improve the prediction of the natural and treatment-induced control of HCV infection; second, these results support the further development of interferon-l for the treatment of chronic hepatitis C; and third, these findings should provide important information for the development of a successful HCV vaccine.