Intrahepatic Gene Expression during Chronic Hepatitis C Virus Infection in Chimpanzees

Bigger, Catherine B.; Guerra, Bernadette; Brasky, Kathleen M.; Hubbard, Gene B.; Beard, Michael R.; Luxon, Bruce A.; Lemon, Stanley M.; Lanford, Robert E.

doi:10.1128/jvi.78.24.13779-13792.2004

Cited by 255 publications

(239 citation statements)

References 93 publications

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“…Although many different functional groups of genes were identified (results not shown), a significant number (39) were known ISGs (Table 3), indicating an ongoing response to endogenous IFN or the dsRNA response to viral infection. This gene set is remarkably similar to that identified in the HCV experimentally infected chimpanzee [7][8][9] ; however, it represents the most comprehensive list of potential ISGs dif- …”

Section: Isgs Are Upregulated In Chcmentioning

confidence: 81%

“…6 Interestingly, both ISG6-16 and ISG-56 are significantly expressed in the livers from acutely and chronically experimentally HCV-infected chimpanzees, suggesting that these along with other ISGs may play a role in limiting virus replication or spread. [7][8][9] In this study, we used microarray analysis of percutaneous liver biopsies to better define the spectrum of ISG expression in the chronically infected HCV liver and to identify potential anti-HCV effector molecules. Similar to experimentally infected chimpanzees, we demonstrate significant upregulation of ISGs, suggesting an ongoing host cellular response to viral infection.…”

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confidence: 99%

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Analysis of ISG Expression in Chronic Hepatitis C Identifies Viperin as a Potential Antiviral Effector *

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Interferon (IFN) ␣ inhibits hepatitis C virus (HCV) replication both clinically and in vitro;however, the complete spectrum of interferon-stimulated genes (ISGs) expressed in the HCV-infected liver or the genes responsible for control of HCV replication have not been defined. To better define ISG expression in the chronically infected HCV liver, DNA microarray analysis was performed on 9 individuals with chronic hepatitis C (CHC). A total of 232 messenger RNAs were differentially regulated in CHC compared with nondiseased liver controls. A significant proportion of these were potential ISGs that were transcriptionally elevated, suggesting an ongoing response to endogenous IFN and/or double-stranded RNA. H epatitis C virus (HCV) is the leading cause of chronic hepatitis and liver disease-related morbidity worldwide. A significant proportion of infected individuals escape the host antiviral response and develop a chronic infection, which can result in progressive liver disease such as cirrhosis and hepatocellular carcinoma. 1 The current and only therapy for chronic hepatitis C (CHC) infection is interferon (IFN) ␣/ribavirin combination therapy that results in response rates to sustained viral clearance in at best 50% of patients. Clearly a significant number of individuals cannot be cured of HCV infection, many of whom will progress to serious liver disease.Viral infection activates the host innate antiviral response, which results in the induction of cellular protective genes, including type I IFNs (IFN-␣ and IFN-␤), proinflammatory cytokines, and a subset of interferonstimulated genes (ISGs) that directly limit viral replication. 2,3 Microarray studies in vitro have revealed that hundreds if not thousands of ISGs may be expressed in response to stimulation with IFN, some of which are known to have direct antiviral and immunomodulatory action. 4 Of the best-characterized antiviral ISGs, MxA, double-stranded RNA (dsRNA)-activated protein kinase R, and 2Ј-5Ј-oligoadenylate synthesase (OAS) are most renowned; however, the complete spectrum of ISGs has not been identified, thus ISGs with potential antiviral action remain unknown. The ISGs that limit HCV replication at the molecular level are ill-defined, although recent work has shown that ISG6-16 can enhance the anti-HCV activity of IFN-␣, 5 and ISG-56 has direct anti-HCV activity through its ability to suppress HCV IRES

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Section: Isgs Are Upregulated In Chcmentioning

confidence: 81%

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confidence: 99%

Analysis of ISG Expression in Chronic Hepatitis C Identifies Viperin as a Potential Antiviral Effector *

et al. 2005

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“…With microarray technology, elevated hepatic ISG expression was found during the acute phase of HCV infection in chimpanzees, which disappeared upon resolution of infection. 45 Chimpanzees with chronic infection had persistently elevated ISG levels in the liver, which were indicative of continuing endogenous production of IFN-α/β. Microarray analyses of chimpanzees without HCV infection treated with IFN-α reveal up-regulation of more than 1000 genes.…”

Section: Insights From Gene Expression Analyses In Chimpanzeesmentioning

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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“…Data from microarray or other gene expression studies have highlighted the importance of ISGs as well as genes of the interferon signaling pathway (IPGs) in the host response to HCV infection [7][8][9][10][11]. Furthermore, association studies have suggested that polymorphisms in these genes may play a role in differential drug response [12,13].…”

Section: Introductionmentioning

confidence: 99%

Association of single nucleotide polymorphisms in interferon signaling pathway genes and interferon-stimulated genes with the response to interferon therapy for chronic hepatitis C

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et al. 2008

Journal of Hepatology

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Intrahepatic Gene Expression during Chronic Hepatitis C Virus Infection in Chimpanzees

Cited by 255 publications

References 93 publications

Analysis of ISG Expression in Chronic Hepatitis C Identifies Viperin as a Potential Antiviral Effector *

Analysis of ISG Expression in Chronic Hepatitis C Identifies Viperin as a Potential Antiviral Effector *

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

Association of single nucleotide polymorphisms in interferon signaling pathway genes and interferon-stimulated genes with the response to interferon therapy for chronic hepatitis C

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