Genome-wide analysis of the transcriptional response to IFN-α in Hepatitis C patients treated with pegIFN-α2a and pegIFN-α2b

Aims and background: The mechanism of action of interferon-alpha (IFN-α) which is used therapeutically to suppress replication of the Hepatitis C Virus (HCV) in chronically infected patients is still unclear.

Methods: To identify target genes that mediate the anti-HCV effect of IFN-α in vivo 39 HCV patients were treated with a standard therapy (PEG-IFNα-2a (n=18) or PEG-IFNα-2b (n=21) + ribavirin) in two independent studies. 12h before and 12h after the first injection of IFN peripheral blood cells were assayed for the expression of IFN-inducible genes (ISGs) using DNA microarrays and quantitative real-time RT-PCR. HCV-RNA levels were determined 12h before and 36h after IFN injection to assess the immediate antiviral effect of IFN. To investigate the predictive value of the gene expression profiles for clinical and virological outcome the data were analysed using the SAM and PAM software packages.

Results: The data show that a rapid initial virological response (IVR, >1,5 log drop after 36h) could be predicted by analysis of the transcriptional response to both IFNs. 19 (PEG-IFNα-2a) and 39 (PEG-IFNα-2b) genes, respectively, were associated with a good initial antiviral response. These genes mostly represented ISGs with known antiviral function. A sustained virological response (SVR) could be predicted by 11 (PEG-IFNa-2a) or 25 (PEG-IFNα-2b) genes, respectively. Interestingly, these genes did not overlap with the genes associated with a good IVR and are not known to have direct antiviral function. More importantly, the SVR was predicted correctly in all patients while only some nonresponders were classified incorrectly by this method.

Conclusions: In conclusion, these data suggest that the initial virological response to IFN-α is associated with the induction of known antiviral genes. We hypothesize that the genes identified are involved in the direct antiviral effector mechanisms of IFN-α which is currently being tested in the HCV replicon system. Furthermore, the SVR can be predicted in HCV patients with a high degree of accuracy which could become a useful clinical tool in the future management of IFN therapy.