Hepatitis C virus expression suppresses interferon signaling by degrading STAT1

Lin, Wenyu; Choe, Won Hyeok; Hiasa, Yoichi; Kamegaya, Yoshitaka; Blackard, Jason T.; Schmidt, Emmett V.; Chung, Raymond T.

doi:10.1053/j.gastro.2005.02.006

Cited by 145 publications

(127 citation statements)

References 36 publications

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“…2B). 20 More importantly, HCV core impaired IFN-α/β-induced STAT1 activation and decreased binding of ISGF3 to nuclear IFN-α ISRE. Structure-function studies have shown that the N-terminal of the HCV core region directly binds to STAT1 at its SH2 domain, which can impair subsequent IFN signaling, suggesting a model in which the direct interaction of HCV core with STAT1 blocks its recruitment and phosphorylation by Jak1 (Fig.…”

Section: Hcv and Ifn Signalingmentioning

confidence: 99%

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

et al. 2008

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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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Section: Hcv and Ifn Signalingmentioning

confidence: 99%

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

et al. 2008

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“…18 A number of reports have provided support for the notion that effects of the core on STAT signaling are caused by direct interaction with STAT1 and STAT3. 3,5,21 Others proposed that these effects are caused by modulation of SOCS-1 and SOCS-3 induction, which in turn regulates activation of STATs. 22,23 Our finding that there is a decrease in SOCS-1 induction in livers of transgenic mice injected with ConA compared to controls is consistent with the latter possibility, without excluding the former.…”

Section: Discussionmentioning

confidence: 99%

“…21,22 The finding in core transgenic mice that STAT1 and SOCS-1 activation are suppressed, while STAT3 activation is stimulated, is in agreement with a number of reports. HCV proteins including the core had been shown to inhibit type I interferon signaling by selectively inducing STAT1 degradation and inhibiting its nuclear translocation, 3,4,5,27 an effect that was explained by direct binding of the core to STAT1. 5 STAT1 is believed to play a critical role in IFN-mediated control of HCV, which is supported by the demonstration that STAT1 activation causes inhibition of HCV gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…Among the many reports on HCV genes and their effects on antiviral responses, a number have shown that the HCV core can modulate interferon (IFN) induced signal transducer and activation of transcription factor 1 (STAT1) signaling. [3][4][5] However, the question as to whether this alters cell-mediated immune responses to the infection was not resolved. In this study, we observed transgenic mice expressing the HCV core under control of the elongation factor-1␣ (EF-1␣) promoter in many tissues, including the lymphoid compartment and liver.…”

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HCV core expression in hepatocytes protects against autoimmune liver injury and promotes liver regeneration in mice†

et al. 2006

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“…[108][109][110] Such activation of KCs could be due to their close interaction with HCV-infected hepatocytes, HCV-derived microbial products, or exposure to lipopolysaccharide, because readily detectable HCV core protein and endotoxin in serum were reported in patients with chronic HCV infection. 98,111 Both HCV products, such as core, NS3 and NS4 proteins, and lipopolysaccharide are potent in vitro activators of monocytes/macrophages [61][62][63]108 ; thus it is conceivable that they may collectively play a role in the maintenance of chronic inflammation in the liver, because-at least in vitro-the KCs do not appear to be directly susceptible to HCV infection. 112 …”

Section: Dendritic Cells In Hcv Infectionmentioning

confidence: 99%

Altered innate immunity in chronic hepatitis C infection

2007

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H epatitis C virus (HCV) is a uniquely successful hepatitis virus in its ability to establish chronic infection in more than two-thirds of those who contract it. The inability of the innate and adaptive immune responses to control HCV invasion and replication contribute to development and persistence of chronic infection. Multiple components have been identified in this process, including pathways by which HCV subverts innate immune recognition and activation, delayed organization of an effective adaptive immune response, the tolerogenic liver environment, and the persistently high levels of viral antigens. We summarize recent findings on the interaction between HCV infection and innate immune responses. Hepatitis C Virus, Immune Responses and Hepatocytes-Brief OverviewA critical role for innate and adaptive immunity has been identified in HCV persistence and liver injury. During acute infection, type I interferon (IFN) is induced in the liver; however, HCV viral load does not decrease, suggesting that HCV interferes with antiviral mechanisms. Innate immune cells, including natural killer cells and dendritic cells shape innate immunity and determine adaptive immune activation. Vigorous, multi-epitopespecific, T helper 1-type and sustained CD4ϩ and CD8ϩ T cell responses were found in resolved acute HCV infections. [1][2][3][4] In contrast, in cases that progress to chronic infection, CD4ϩ T cell responses are weak, short-lived, and targeted to a narrow range of epitopes. 1

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Hepatitis C virus expression suppresses interferon signaling by degrading STAT1

Cited by 145 publications

References 36 publications

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

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

HCV core expression in hepatocytes protects against autoimmune liver injury and promotes liver regeneration in mice†

Altered innate immunity in chronic hepatitis C infection

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