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

Abstract

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.

High-throughput Gene Expression Profiling: Its Application in Studying Transfusion-Transmitted Infections

“…Furthermore, they demonstrated that the pre-activation of the endogenous interferon signaling and the celltype differential expression of ISGs are not unique for HCV. Similar findings were identified in patients chronically infected with HBV [15,16]. Put all these together, this is an excellent example on how gene expression profiling can be used to delineate virus-host interactions in order to better understand the molecular mechanisms of viral resistance, leading to the identification of new drug targets [17].…”

“…By comparing the pretreatment hepatic gene expression levels between treatment responders and non-responders of patients chronically infected with HCV, Chen et al [12,13] identified 18 genes (out of 19,000 host genes or transcripts), whose differential expression levels are associated with treatment outcomes. More interestingly, they demonstrated that the cell-type specific protein expression of ISGs in a novel ubiquity in-like pathway (ISG 15/USP 18) correlated well with treatment outcomes, with prediction accuracy higher than that predicted by the polymorphism of IL28B [14,15]. Furthermore, they demonstrated that the pre-activation of the endogenous interferon signaling and the celltype differential expression of ISGs are not unique for HCV.…”

Multiple functions of USP18

“…14 The antiviral effect is not due to enhanced ISGylation of ISG15 in the absence of USP18, because Isg15-deficient mice do not exhibit any antiviral impairment after infection with LCMV or VSV. 56 In Addition, Usp18 knockout mice exhibit less replication of several other viruses, such as HBV, 61,62 Sindbis virus, 63 influenza B virus, 46 HIV, 64 and others in which the ISGylation pathway is involved [65][66][67][68][69] (Table 2).…”

Induction of interleukin 6 impairs the anti‐HBV efficiency of IFN‐α in human hepatocytes through upregulation of SOCS3

“…Antiviral responses to IFN‐α are mediated by many antiviral proteins induced through activation of the JAK‐STAT signaling pathway . The activated STAT1/2 heterodimerize with interferon regulatory factor 9 (IRF‐9) to form the interferon‐stimulated gene factor 3 (ISGF‐3) transcription factor complexes and then translocate into the nucleus, where they bind to the interferon‐stimulated response element (ISRE) in the promoter of interferon‐stimulated genes (ISGs), including myxovirus resistance A (MxA), oligoadenylate synthetase (OAS), and RNA‐activated protein kinase (PKR), all of which restrict HBV replication in human hepatocytes . Nevertheless, about 70% of CHB patients respond poorly to IFN‐α treatment .…”

“…8 The activated STAT1/2 heterodimerize with interferon regulatory factor 9 (IRF-9) to form the interferon-stimulated gene factor 3 (ISGF-3) transcription factor complexes and then translocate into the nucleus, where they bind to the interferon-stimulated response element (ISRE) in the promoter of interferon-stimulated genes (ISGs), including myxovirus resistance A (MxA), oligoadenylate synthetase (OAS), and RNA-activated protein kinase (PKR), all of which restrict HBV replication in human hepatocytes. 9,10 Nevertheless, about 70% of CHB patients respond poorly to IFN-α treatment. [11][12][13] The molecular mechanisms of IFN-α resistance of HBV are not completely understood, and a detailed understanding of the processes involved would enhance the anti-HBV efficacy of IFN-α therapy.…”