Cell-Type Specific Interferon Stimulated Gene Staining in Liver Underlies Response to Interferon Therapy in Chronic HBV Infected Patients

Interferon-alpha is approved as one of the main therapeutic treatments for chronic hepatitis B virus infection, but only a small number of patients achieve sustained virological response. The molecular mechanisms underlying IFN-alpha resistance in those patients who do not respond remain elusive. Previous work in our laboratory identified the pre-activation of IFN signaling leading to increased expression of a subset of interferon stimulated genes in the pretreatment liver tissues of chronic HBV infected patients correlated with treatment non-response. We studied the cell-type specific gene expression of interferon stimulated genes in the liver of chronic HBV infected patients and the cellular basis of the phenotype through ISG15 and MxA protein expression. Immunohistochemical analysis was used to detect the expression of ISG15 and MxA protein in the pretreatment liver tissues of chronic HBV infected patients and the expression patterns were correlated with treatment outcomes. In the non-responders, ISG15 and MxA protein expression in the pretreatment liver tissues was more pronounced in hepatocytes while in the responders, ISG15 and MxA protein expression was more focused in macrophages. ISG15 and MxA proteins were occasionally expressed in hepatocytes in normal livers. There were significant differences in the cell-type specific protein expression of ISG15 and MxA in the pretreatment liver tissues of chronic HBV infected patients between treatment responders and non-responders. An easy prediction method based on immunohistochemical stains of a subset of interferon stimulated genes may be developed to predict treatment outcomes of IFN therapy in chronic HBV infected patients.