Genome-Wide Analysis of the Transcriptional IFN-α Response in Patients Treated for Hepatitis C

Abstract

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 21 HCV patients were treated with a standard therapy (PEG-IFNα–2b + ribavirin). 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. In addition, to investigate the possible predictive value of the gene expression profiles for clinical and virological outcome the data were analysed using the PAM software package (Prediction Analysis for Microarrays, http: //www-stat.stanford.edu/%7Etibs/ PAM/). Results: In 21 patients (genotype 1: n=14, genotype 2/3: n=7) the correlation of gene expression with the initial viral drop could be analysed while data from 20 patients (1 patient lost in follow-up) were available for analysis of the sustained virological response (SVR). 14 patients had a SVR. The data show that a rapid initial virological response (>1,5 log drop after 36h) and SVR (neg. HCV-PCR 6 months after therapy) could predicted by analysis of the transcriptional response to IFN-α and the basic gene expression in this cohort of patients. Both clinical conditions were associated with specific gene expression profiles. Conclusions: In conclusion, these data suggest that both the initial virological response and the sustained virological response are associated with specific gene expression profiles and can be predicted in HCV patients before or at the very beginning of IFN treatment. These findings are of possible clinical value in particular for patients with genotype 1 infection and other problematic cases that do not respond well to combination therapy. Furthermore, it suggests that the SVR is largely depended upon the genetic background of the patient provided he or she is adherent to therapy.