Liver expression of proteins controlling interferon-mediated signalling as predictive factors in the response to therapy in patients with hepatitis C virus infection

Abstract

Combination therapy with interferon-alpha (IFNalpha) and ribavirin is the current treatment of choice for hepatitis C virus (HCV) infection. However, an important number of patients fail to respond to this therapeutic strategy. Factors determining IFN responsiveness are not well understood, and assessment of biomarkers that predict the response to IFN therapy in HCV patients is necessary. Several studies show that particular HCV proteins are able to block IFN function through interaction with important IFN-signal mediators, such as signal transducers and activators of transcription (STATs). We performed immunostaining analysis of STATs in liver tissue from IFN-responder vs. non-responder HCV patients in order to compare the expression profile of these proteins between both groups. Tissue arrays of liver biopsies were used to study the expression of STAT1, STAT2, STAT5 and PIAS1 (protein inhibitor of activated STAT1). Robust and higher expression levels of STAT1, STAT2 and STAT5 in liver tissue from HCV patients were found when compared with samples from healthy donors. However, no significant differences were observed between IFN-responder and -non-responder groups, but rather increasing levels of STAT1, STAT2 and STAT5 paralleled the degree of liver injury. Importantly, PIAS1 expression in the nucleus of most hepatocytes in HCV tissue biopsy sections, particularly of non-responder HCV patients, strongly indicated a regulatory effect on STAT1-DNA binding, likely affecting the IFN late signalling. In conclusion, our evidence indicates that intense PIAS1 nuclear staining, widely distributed in hepatocytes of infected livers, could be a good predictive factor of a defective response to IFN treatment, and a biomarker that is easily detectable by immunostaining during standard histopathological liver biopsy analysis.