Article

The interferon stimulated gene 15 functions as a proviral factor for the hepatitis C virus and as a regulator of the IFN response

Department of Gastroenterology and Hepatology, University Hospital of Essen, Hufelandstr 55, Essen 45122, Germany.
Gut (Impact Factor: 13.32). 08/2010; 59(8):1111-9. DOI: 10.1136/gut.2009.195545
Source: PubMed

ABSTRACT Non-response to combination therapy by patients with hepatitis C virus (HCV) has previously been associated with a strong hepatic upregulation of interferon stimulated genes (ISGs) including ISG15. Therefore, the aim of this study was to further elucidate the functional role of this molecule.
ISG15 expression was suppressed by siRNAs or enhanced by over-expression in genomic and subgenomic human or murine HCV replicon systems. In addition, ISG15 expression was analysed in liver samples of patients with HCV prior to antiviral therapy and correlated with clinical and virological parameters.
Short- or long-term knockdown of ISG15 expression suppressed HCV replication comparable to IFNs without evidence for the induction of resistant mutations. Triple therapy consisting of ISG15 knockdown, interferon alpha (IFNalpha) and ribavirin led to complete suppression of the HCV NS5A protein, corresponding to 99% suppression of HCV-RNA compared to 75% suppression by IFNalpha and ribavirin only. Combination treatment of ISG15 knockdown and IFN was associated with enhanced and prolonged expression of selected ISGs. Consistent with these in vitro data, high hepatic ISG15 levels correlated with the unfavourable HCV genotype 1, a high hepatic HCV load and a low antiviral response to IFN during the initial phase of treatment.
ISG15 plays an important role in the HCV replication cycle. Therefore, therapies based on the suppression of ISG15 may provide a promising strategy to overcome non-response to standard combination treatment in the future. Furthermore, analysis of ISG15 prior to therapy may be useful to predict short-term and long-term outcome and thus tailor antiviral therapy with pegIFN and ribavirin.

1 Follower
 · 
169 Views
 · 
0 Downloads
  • Source
    • "IFN stimulated gene 15 ISG15 MH1 rep oe/kd [118] HuH7.5 inf oe [119] HuH7.25. CD81 inf kd [84] Protein kinase R "
    [Show abstract] [Hide abstract]
    ABSTRACT: Infections with the hepatitis C virus (HCV) are a major cause of chronic liver disease. While the acute phase of infection is mostly asymptomatic, this virus has the high propensity to establish persistence and in the course of one to several decades liver disease can develop. HCV is a paradigm for the complex interplay between the interferon (IFN) system and viral countermeasures. On one hand HCV induces an IFN response, but on the other hand within the infected cell HCV is rather sensitive against the antiviral state triggered by IFNs. Numerous IFN-stimulated genes (ISGs) have been reported to suppress HCV replication, but in only a few cases we begin to understand the molecular mechanisms underlying antiviral activity. It is becoming increasingly clear that blockage of viral replication is mediated by the concerted action of multiple ISGs that target different steps of the HCV replication cycle. This review briefly summarizes the activation of the IFN system by HCV and then focuses on ISGs targeting the HCV replication cycle and their possible mode of action.
    Journal of Hepatology 08/2013; 59(6). DOI:10.1016/j.jhep.2013.07.033 · 10.40 Impact Factor
  • Source
    • "This suggests that, ISG-15 induction, previously shown to be important in type-I IFN-mediated innate immunity against multiple, non-HCV viral infections [Lenschow et al., 2007], appears to sometimes promote HCV replication and hinder sustained virologic response to HCV therapy based on different HCV replication models, such as when ISG-15 is qualitatively inappropriately expressed [Chen et al., 2010]. Importantly, siRNA knockdown of ISG-15 expression significantly enhances response to standard combination therapy against genotypes 1 and 2 HCV in vitro through the selectively prolonged expression of several ISG, including IFI6, CXCL10, GBP1, HERC5, USP18, IFITM3, OAS1, and MX1 [Chua et al., 2009; Broering et al., 2010]. This study demonstrates in vitro and in vivo expression of ISG-15 as a marker for poor virologic response to treatment in patients co-infected with HIV and HCV. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Increased baseline expression and lack of induction of interferon-stimulated genes (ISG) are strong negative predictors of therapeutic response to PegIFN/RBV in patients co-infected with HIV and hepatitis C virus (HCV). This study specifically addressed whether ISG-15 expression influences therapeutic responses in 20 HIV/HCV genotype-1 subjects undergoing HCV treatment. Non-responders had significantly higher baseline expression and selective induction of ISG-15 after IFN-α treatment relative to participants with sustained virological response. High baseline levels of ISG-15 were also associated with less induction of ISG with treatment. These results support a role for ISG-15 as a prognostic indicator and resistance factor to IFN-α. J. Med. Virol. 85: 959-963, 2013. © 2013 Wiley Periodicals, Inc.
    Journal of Medical Virology 06/2013; 85(6):959-63. DOI:10.1002/jmv.23576 · 2.22 Impact Factor
  • Source
    • "The E. coioides IRF-1, IRF-2 and IRF-7 genes have been cloned and characterized and IRF-7 was confirmed as being vitally important for SGIV replication [39,40]. Human ISG15 expression is strongly up-regulated during viral infections, such as human cytomegalovirus (HCMV) and herpes simplex virus (HSV), and ISG15 up-regulation was considered to be involved in different strategies relating to the antiviral response [41-44]. IFP35 and ISG56 were also involved in the cellular antiviral response against virus infection [38,45]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Orange-spotted grouper (Epinephelus coioides) is an economically important marine fish cultured in China and Southeast Asian countries. The emergence of infectious viral diseases, including iridovirus and betanodavirus, have severely affected food products based on this species, causing heavy economic losses. Limited available information on the genomics of E. coioides has hampered the understanding of the molecular mechanisms that underlie host-virus interactions. In this study, we used a 454 pyrosequencing method to investigate differentially-expressed genes in the spleen of the E. coioides infected with Singapore grouper iridovirus (SGIV). Using 454 pyrosequencing, we obtained abundant high-quality ESTs from two spleen-complementary DNA libraries which were constructed from SGIV-infected (V) and PBS-injected fish (used as a control: C). A total of 407,027 and 421,141 ESTs were produced in control and SGIV infected libraries, respectively. Among the assembled ESTs, 9,616 (C) and 10,426 (V) ESTs were successfully matched against known genes in the NCBI non-redundant (nr) database with a cut-off E-value above 10-5. Gene ontology (GO) analysis indicated that "cell part", "cellular process" and "binding" represented the largest category. Among the 25 clusters of orthologous group (COG) categories, the cluster for "translation, ribosomal structure and biogenesis" represented the largest group in the control (185 ESTs) and infected (172 ESTs) libraries. Further KEGG analysis revealed that pathways, including cellular metabolism and intracellular immune signaling, existed in the control and infected libraries. Comparative expression analysis indicated that certain genes associated with mitogen-activated protein kinase (MAPK), chemokine, toll-like receptor and RIG-I signaling pathway were alternated in response to SGIV infection. Moreover, changes in the pattern of gene expression were validated by qRT-PCR, including cytokines, cytokine receptors, and transcription factors, apoptosis-associated genes, and interferon related genes. This study provided abundant ESTs that could contribute greatly to disclosing novel genes in marine fish. Furthermore, the alterations of predicted gene expression patterns reflected possible responses of these fish to the virus infection. Taken together, our data not only provided new information for identification of novel genes from marine vertebrates, but also shed new light on the understanding of defense mechanisms of marine fish to viral pathogens.
    BMC Genomics 11/2011; 12:556. DOI:10.1186/1471-2164-12-556 · 4.04 Impact Factor
Show more