Silencing of USP18 Potentiates the Antiviral Activity of Interferon Against Hepatitis C Virus Infection

Randall, Glenn; Chen, Limin; Panis, Maryline; Fischer, A; Lindenbach, Brett D.; Sun, Jing; Heathcote, Jenny; Rice, Charles M.; Edwards, A.M.; McGilvray, Ian

doi:10.1053/j.gastro.2006.08.043

Cited by 155 publications

(149 citation statements)

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“…Other host factors in the IFN-regulatory pathway might be associated with the responses to antiviral treatment [216; 217]. Interferon-sensitive gene 15 (ISG15) and ubiquitin-specific protease 18 (USP18), which are linked biochemically in IFN-regulatory pathway, modulate the IFN responses against HCV [216]. USP18 up-regulation is one of the factors predicting a lack of response to IFN treatment [217].…”

Section: Role Of Immune Responses In Outcome Following Ifn and Ribavimentioning

confidence: 99%

Immune responses during acute and chronic infection with hepatitis C virus

Ishii

Koziel

2008

Clinical Immunology

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Hepatitis C virus (HCV) induces persistent infection and causes chronic liver disease in most infected patients. Vigorous HCV-specific CD4+ and CD8+ T cell responses against HCV multiple epitopes are necessary for spontaneous viral clearance during the acute phase, but the virus appears to have multiple strategies to evade these defenses. There are relatively few studies on the role of immune responses during the chronic phase of infection. CD4+ T cell responses appear to protect against liver injury and may be important to clearance during interferon and ribavirin based therapy. Classic cytotoxic T cells (CTL) may primarily damage the liver in chronic HCV, but there may be subpopulations of T cells that protect against liver inflammation. Resolution of these outstanding questions is important to the development of a prophylactic vaccine as well as improving therapeutic options for those with chronic infection.

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Section: Role Of Immune Responses In Outcome Following Ifn and Ribavimentioning

confidence: 99%

Immune responses during acute and chronic infection with hepatitis C virus

Ishii

Koziel

2008

Clinical Immunology

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“…Of these 8 genes, ISG15 and ubiquitin specific peptidase 18 (USP18) have been further studied in a tissue culture model of HCV infection. 49 USP18 is a cysteine de-ubiquitinase that cleaves ISG15, a ubiquitinlike molecule, from its target. Down-regulation of USP18 was shown to enhance IFN-α/β responses in inhibiting HCV replication in vitro.…”

Section: Ifn Responses In Peripheral Blood and Liver In The Hcv-infecmentioning

confidence: 99%

Mechanisms of action of interferon and ribavirin in chronic hepatitis C: Summary of a workshop

et al. 2007

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The current recommended therapy for chronic hepatitis C is the combination of peginterferon and ribavirin, which results in a sustained clearance of hepatitis C virus (HCV) in at least half of patients. However, the mechanisms by which interferon alpha (IFN-α) and ribavirin act against HCV are not well defined. The importance of understanding the biological pathways, cellular effects, and antiviral activities of these agents is underscored by clinical observations that nonresponders frequently have little or no decrease in HCV RNA levels during treatment, suggesting intrinsic resistance to IFN-α. Cell culture and animal models of HCV have shown that the infection itself may block IFN-α induction and action. Still other findings suggest that individual innate and adaptive immune responses, host genetic factors, viral genetic diversity, and clinical comorbidities account for part of nonresponse to therapy. To provide an overview of the current knowledge of the mechanisms of action of IFN-α and ribavirin against HCV and offer guidance for future research, the American Association for the Study of Liver Diseases held a single topic conference entitled "Interferon and Ribavirin in Hepatitis C Virus Infection: Mechanisms of Response and Non-Response" on March [1][2][3] 2007. This article summarizes that conference. Interferons (IFNs): An OverviewThe IFNs (Dr. Howard Young, National Cancer Institute, National Institutes of Health)The type 1 IFNs [interferon alpha and beta (IFN-α/β)] comprise a family of distinct proteins1 that are produced by a wide variety of cells, including fibroblasts, epithelial cells, and hepatocytes, 2 although plasmacytoid dendritic cells (DCs) are probably the major source in most viral infections. In contrast, type II IFN [interferon gamma (IFN-γ)] is a single gene cytokine unrelated in structure to IFN-α/β that is produced largely by macrophages, natural Copyright © 2007 by the American Association for the Study of Liver Diseases.Address reprint requests to: Raymond T. Chung, M.D., Gastrointestinal Unit, GRJ724, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. rtchung@partners.org; fax: 617-643-0446.. Potential conflict of interest: Dr. Lemon is a consultant for Novartis, GlaxoSmithKline, Hoffman-LaRoche, Genelabs Technology, Abbott, Pharmasett. He also received grants from Schering-Plough and Tibotec. Dr. Chung received grants from Roche and ScheringPlough. NIH Public Access Author ManuscriptHepatology. Author manuscript; available in PMC 2009 December 29. Published in final edited form as:Hepatology. 2008 January ; 47(1): 306-320. doi:10.1002/hep.22070. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript killer (NK) cells, and T lymphocytes. Both types of IFNs interact with cells via distinct cellular receptors. The details of the signaling mechanisms by which IFN-α/β and IFN-γ induce the transcription of interferon-stimulated genes (ISGs) and depress the transcription of others are still being defined. 3 However, it is increasingly clear that the c...

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“…USP18 are believed to play essential roles in many biological functions, such as host innate immune response (Randall et al, 2006), brain cell injury , fetal development (Rempel et al, 2007), pancreatic beta cell inflammation and apoptosis (Santin et al, 2012) and so on. Recently the role of mammalian USP18 in viral infections was most comprehensively studied, indicating that this role is mediated both via its ISG15 protease action and in proteaseindependent fashions (Chen et al, 2011).…”

Section: Discussionmentioning

confidence: 99%