G–300A interferon regulatory factor-1 promoter polymorphism is associated with the outcome of hepatitis C virus infection

Background and Objectives: Interferon-α (IFN-α) is an important mediator for the host's innate antiviral defense system that also is used for the treatment of persistent viral infections. The aim of this study was to investigate whether two functional polymorphisms in genes which are involved in IFN-α signal transduction and effector function are associated with (i) the natural outcome of hepatitis C virus (HCV) infection and (ii) the responsiveness of chronic hepatitis C patients to IFN-α therapy. Methods: Forty-four individuals who had resolved HCV infection spontaneously and 147 patients who developed chronic hepatitis C had been characterized before with respect to demographic and clinical parameters. Samples of genomic DNA were genotyped at positions –300 and –88 within in the promoter regions of the interferon regulatory factor–1 (IRF–1) and myxovirus resistance protein–1 (MxA) genes, respectively, by 5'-nuclease assays using differentially fluorescent dye-labelled allele-specific probes. Results: Patients with self-limited infections displayed no significant difference in comparison to those with chronic infections with respect to –300 IRF–1 or –88 MxA genotype distributions or minor allele frequency, respectively. Among patients with chronic infections, however, those with the –300AA IRF–1 genotype, which is associated with a higher IRF–1 transcriptional activity, were, with only one exception, absent from the group infected with HCV genotype 3a. In contrast to what might have been assumed, they also failed to appear in higher numbers among those with self-limited infections. This is even the case when patients with hepatitis A or hepatitis B virus infections, which might occasionally function as an alternative, non-genetic mechanism for virus elimination, were disregarded. Furthermore, chronic hepatitis C patients with the –300AA IRF–1 genotype infected predominately with HCV genotype 1 were found to respond more often to therapy than did those with the non–300AA IRF–1 genotypes. Conclusion: Our findings support the concept that a genetic background sensitizing for IFN-α efficacy, or a locus which is in linkage disequilibrium with –300 IRF–1, favors HCV elimination in individuals who had contact to virus genotype 3a and also might support HCV eradication in response to IFN-α therapy in chronic hepatitis C patients.

HCV - anti-HCV - hepatitis C - persistent infection - self-limited infection