Antiviral Effect and Virus-Host Interactions in Response to Alpha Interferon, Gamma Interferon, Poly(I)-Poly(C), Tumor Necrosis Factor Alpha, and Ribavirin in Hepatitis C Virus Subgenomic Replicons

Lanford, Robert E.; Guerra, Bernadette; Lee, Helen; Averett, Devron R.; Pfeiffer, Brad E.; Chavez, Deborah J.; Notvall, Lena; Bigger, Catherine B.

doi:10.1128/jvi.77.2.1092-1104.2003

Cited by 205 publications

(163 citation statements)

References 70 publications

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“…This is further validated in vitro, in which treatment of cells harboring HCV replication with IFN-␣ results in a dosedependent decrease in HCV RNA. 19,20 Furthermore, long-term treatment of HCV replicon cells with IFN-␣ can "cure" these cells completely of HCV replication. 21 However, despite this, the complete spectrum of ISGs in the HCV-infected liver has not been identified, nor have the ISGs responsible for the control of HCV replication been defined.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2005

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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: Discussionmentioning

confidence: 99%

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

et al. 2005

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“…Total RNA prepared from liver and PBMC was used to perform microarray analyses 10,11 and quantitative reverse transcription polymerase chain reaction (RT-PCR; TaqMan) 19 as described in Supplemental Methods (Supplementary materials is available at the HEPATOLOGY website: http://interscience.wiley.com/jpages/0270-9139/ suppmat/index.html). Uninfected chimpanzees were inoculated subcutaneously with 5 million IU IFN-␣; blood and liver samples were obtained at 0, 4, 8, and 24 hours post-inoculation, followed by 30 days of rest before a second exposure to a different IFN-␣ (Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Although IP-10 was originally identified as an IFN-␥-specific transcript, its induction by IFN-␣ is well documented. 19 In contrast, MIG is still considered to be an IFN-␥-specific transcript and a sensitive marker for IFN-␥ function. 39 The current analysis demonstrated that MIG can be induced in hepatocytes by IFN-␣, although induction by IFN-␥ was 5-to 10-fold greater.…”

Section: Tissue-specific Responses To Ifn-␣mentioning

confidence: 99%

“…10,11 The importance of IFN-␣ in HCV clearance has been demonstrated in several studies: (1) the high rate of sustained viral clearance of chronic infections after combined therapy with peg-IFN-␣ and ribavirin, 4,5 (2) the near 100% viral clearance rate using IFN-␣ monotherapy in acutely infected individuals, 17 and (3) the sensitivity of HCV-replicons to IFN-␣. [18][19][20] Previous studies in chimpanzees using traditional IFN-␣ therapy with and without ribavirin, as well as adenovirus-based gene therapy to induce high-level expression of IFN-␣ in the liver, failed to induce a reduction in viral load despite high levels of circulating IFN-␣ for extended times after adenovirus gene therapy. 21,22 One concern was whether human IFN-␣ was effective in the chimpanzee.…”

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confidence: 99%

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Genomic response to interferon-α in chimpanzees: Implications of rapid downregulation for hepatitis C kinetics

et al. 2006

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The mechanism of the interferon-alpha (IFN-␣)-induced antiviral response during hepatitis C virus (HCV) therapy is not completely understood. In this study, we examined the transcriptional response to IFN-␣ in uninfected chimpanzees after single doses of chimpanzee, human, or human-pegylated IFN-␣. Liver and peripheral blood mononuclear cell (PBMC) samples were used for total genome microarray analysis. Most induced genes achieved maximal response within 4 hours, began to decline by 8 hours, and were at baseline levels by 24 hours postinoculation, a time when high levels of circulating pegylated IFN-␣ were still present. W orldwide, approximately 170 million people are chronically infected with hepatitis C virus (HCV), which frequently progresses to serious liver disease, including cirrhosis and hepatocellular carcinoma. 1,2 The current therapy involves the combination of pegylated (peg)-interferon alpha (IFN-␣) and ribavirin (reviewed in Feld and Hoofnagle 3 ) and has response rates for sustained viral clearance of approximately 40% to 50% and 80% to 90% for genotypes 1 and 2/3, respectively. 4,5 However, a significant proportion of the population still develops serious disease as a consequence of HCV infection. HCV infection is the leading cause for liver transplantation in the United States 1,2 and liver cancer due to HCV infection is one of the most rapidly increasing types of cancer in the United States. 6 Little is understood regarding the factors leading to successful or failed viral clearance during IFN-␣ therapy. The early kinetics of viral RNA loss from the circulation during IFN-␣ therapy suggests the presence of two phases. Phase I occurs during the first 24 to 48 hours and is presumed to be due to the decrease in secretion of new virions, whereas phase II kinetics vary between individuals, are predictive of the outcome of therapy, and are thought to be a measurement of loss of infected cells. [7][8][9] We 10,11 and others 12 have previously performed gene expression analyses on liver from chimpanzees that experienced acute-resolving or chronic HCV infections. The

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“…In studies using HCV replication models, mutagenic effects of ribavirin have been identified by several 54,[56][57][58][59][60] but not all authors. 61 When infectivity was used as a functional readout for mutagenesis, diminished infectivity was found with ribavirin treatment of HCV cultures.58 , 60 The concentrations of ribavirin needed to achieve mutagenic effects were high (up to 400 uM) and may exceed those achieved in vivo.…”

Section: Ribavirin: Mechanism Of Action Clinical Insightsmentioning

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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Antiviral Effect and Virus-Host Interactions in Response to Alpha Interferon, Gamma Interferon, Poly(I)-Poly(C), Tumor Necrosis Factor Alpha, and Ribavirin in Hepatitis C Virus Subgenomic Replicons

Cited by 205 publications

References 70 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 *

Genomic response to interferon-α in chimpanzees: Implications of rapid downregulation for hepatitis C kinetics

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

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