IFN‐α antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling‐3

Bode, Johannes G.; Ludwig, Stephan; Ehrhardt, Christina; Albrecht, Ute; Erhardt, Andreas; Schaper, Fred; Heinrich, Peter C.; Häussinger, Dieter

doi:10.1096/fj.02-0664fje

Cited by 277 publications

(230 citation statements)

References 26 publications

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“…We have also shown that the inhibition of IRF-1 expression occurred at the transcriptional level through both the STAT-1 and NF-B consensus sequences on the IRF-1 promoter. In agreement with these data it has recently been reported that core protein inhibits both the activation and nuclear translocation of STAT-1 in IFN-treated cells (7,47). In addition, in core-expressing cells NF-B nuclear translocation and activity is also suppressed (29).…”

Section: Discussionsupporting

confidence: 86%

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Repression of Interferon Regulatory Factor 1 by Hepatitis C Virus Core Protein Results in Inhibition of Antiviral and Immunomodulatory Genes

Ciccaglione

Stellacci

Marcantonio

et al. 2007

J Virol

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Hepatitis C virus (HCV) proteins are known to interfere at several levels with both innate and adaptive responses of the host. A key target in these effects is the interferon (IFN) signaling pathway. While the effects of nonstructural proteins are well established, the role of structural proteins remains controversial. We investigated the effect of HCV structural proteins on the expression of interferon regulatory factor 1 (IRF-1), a secondary transcription factor of the IFN system responsible for inducing several key antiviral and immunomodulatory genes. We found substantial inhibition of IRF-1 expression in cells expressing the entire HCV replicon. Suppression of IRF-1 synthesis was mainly mediated by the core structural protein and occurred at the transcriptional level. The core protein in turn exerted a transcriptional repression of several interferonstimulated genes, targets of IRF-1, including interleukin-15 (IL-15), IL-12, and low-molecular-mass polypeptide 2. These data recapitulate in a unifying mechanism, i.e., repression of IRF-1 expression, many previously described pathogenetic effects of HCV core protein and suggest that HCV core-induced IRF-1 repression may play a pivotal role in establishing persistent infection by dampening an effective immune response.Infection with hepatitis C virus (HCV) represents the major cause of liver disease, affecting more than 170 million individuals worldwide (26). After a subclinical phase, more than 80% of patients progress to persistent HCV infection, which is the leading cause of chronic liver disease associated with cirrhosis and hepatocellular carcinoma (13). The persistence of the virus in the majority of infected individuals is linked to the ability of HCV to evade and/or antagonize the host immune response at both the local and systemic levels. Accordingly, although hepatocytes are a major target of HCV infection, the virus can also replicate in immune cells, including effector cells (1,11). In this respect, resistance to interferon (IFN) therapy is a hallmark of evolution in persistence, indicating that knocking down the antiviral and immunomodulating effects of IFN is a successful strategy for evading the host immune surveillance (21). The production and secretion of IFN type I is pivotal in inducing a global antiviral state through paracrine IFN production and the subsequent activation of interferon-stimulated genes (ISGs) within the infected cells and in the surrounding tissues (70). The role of IFN in HCV infection is thus crucial (21). Functional genomic analyses from cohorts of human subjects with chronic infection have shown that infection is associated with a gene expression profile marked by ISGs whose level of expression is related to different degrees of liver fibrosis and cirrhosis (67). Similarly, gene expression profiling has demonstrated that acute resolving infections in chimpanzees are associated with high levels of hepatic ISG expression (4).The single-stranded RNA genome of HCV is translated into a polypeptide precursor of 3,010 amino aci...

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Section: Discussionsupporting

confidence: 86%

“…Conversely, (3,6,7,12,47,48,50,54). Variations in the experimental system used, structural or genotypic differences in the protein and, possibly, the amount of protein used may all be implicated in the reported discrepancies.…”

Section: Discussionmentioning

confidence: 99%

Repression of Interferon Regulatory Factor 1 by Hepatitis C Virus Core Protein Results in Inhibition of Antiviral and Immunomodulatory Genes

Ciccaglione

Stellacci

Marcantonio

et al. 2007

J Virol

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“…The latter is apparently mediated neither by PPAR␥ or SOCS-7 nor by SOCS-1 or SOCS-3, as suggested elsewhere. 12,43,44 On the contrary, genotype 1b appears to induce IRS-1 downregulation (probably through proteasomal degradation, as it is blocked by the proteasomal inhibitor MG132), at least in part, through the mTOR pathway. This increase of mTOR activity is in agreement with previous observations, 34 suggesting that stimulation of mTOR by HCV protects cells against apoptosis and contributes to the maintenance of steady-state levels of HCV replication.…”

Section: Discussionmentioning

confidence: 99%

“…Ubiquitin-mediated proteasomal degradation, brought about by SOCS-1 and 3, is another negative modulatory mechanism of IRS-1 and IRS-2 expression. 19 However, reported evidence in HCV infection is controversial: while some works attested that HCV 1b induces an increase of SOCS-1/SOCS-3 expression both in vivo and in vitro, 12,[42][43][44] others documented a decreased SOCS-1 level. 45 In our model, SOCS-1 and SOCS-3 levels are unchanged irrespectively of the genotype, while the level of SOCS-7, recently shown to be involved in IRS-1 degradation, 20 is increased in genotype 3a only.…”

Section: Discussionmentioning

confidence: 99%

The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms

et al. 2007

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Both molecular and clinical evidence support a link between HCV infection and insulin resistance. We examined the in vitro interaction between the HCV core protein of genotypes 3a and 1b with the insulin-signaling pathway. We measured the expression levels of insulin receptor substrate 1 (IRS-1), IRS-2, and other factors involved in the insulin signal pathway in a human hepatoma cell line (Huh-7) transiently expressing the HCV core protein of genotypes 3a or 1b by molecular biology and biochemical techniques. The IRS-1 (but not IRS-2) protein level was significantly reduced in Huh-7 expressing the core protein of both genotypes 3a and 1b, as compared to cells transfected with the empty vector. However, while the core protein of genotype 3a promoted IRS-1 degradation through the downregulation of peroxisome proliferator-activated receptor ␥ (PPAR␥) and by upregulating the suppressor of cytokine signal 7 (SOCS-7), the core protein of genotype 1b activated the mammalian target of rapamycin (mTOR). We confirmed these findings by using agonists for PPAR␥ (rosiglitazone) or short interfering RNAs for SOCS-7. Conclusion: Despite the small sequence divergence of the HCV core proteins of genotypes 3a and 1b, the 2 proteins appear to interfere with the insulin signaling pathway using genotype-specific mechanisms.

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“…5,6,29 However, although SOCS-3 has been reportedly elevated in the liver of chronic hepatitis C patients with IR, 7 its role in reducing the response to therapy has been challenged by experimental 30 and clinical data. 31 A second hypothesis is based on data suggesting that high concentrations of insulin directly inhibit interferon alpha signaling, independently of SOCS-3.…”

Section: Discussionmentioning

confidence: 99%

Homeostasis model assessment of insulin resistance does not seem to predict response to telaprevir in chronic hepatitis C in the REALIZE trial

et al. 2013

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Baseline homeostasis model assessment-estimated insulin resistance (HOMA-IR), a marker for insulin resistance, has been associated with poor virologic response to peginterferon alpha/ribavirin (PR) in chronic hepatitis C. We evaluated the association between baseline HOMA-IR and pretreatment factors on sustained virologic response (SVR) to telaprevir (TVR) in genotype 1 patients with hepatitis C and prior peginterferon/ribavirin (PR) treatment failure. Patients were randomized to 12 weeks of TVR (750 mg q8h) plus peginterferon (180 lg/week) and ribavirin (1,000-1,200 mg/day) (with or without a 4-week lead-in) followed by PR, or PR alone (PR48), for 48 weeks. Univariate and multiple logistic regression analyses explored the prognostic significance of baseline HOMA-IR alone and adjusted for other pretreatment factors and SVR. The TVR arms were pooled for the purposes of this analysis. In all, 662 patients were randomized; 578 had baseline HOMA-IR and other prognostic data and were included in this analysis. Median baseline HOMA-IR was 2.6 (interquartile range [IQR] 1.7-4.3); 207 (36%), 206 (36%), and 165 (29%) patients had baseline HOMA-IR <2, 2 to <4, and 4, respectively. Male gender, higher body mass index, triglycerides, gamma-glutamyl transpeptidase, maximum alanine aminotransferase/aspartate aminotransferase, and fibrosis stage were associated with higher baseline HOMA-IR. Baseline HOMA-IR was associated with SVR in univariate analysis, but not after adjustment for other baseline prognostic factors (TVR: OR 5 0.95, 95% confidence interval [CI]: 0.71,1.29; PR48: 0.60; 95% CI: 0.25,1.43). Conclusion: In patients with prior PR treatment failure, baseline HOMA-IR correlated with SVR in univariate but not multivariate analyses, suggesting other factors have a more direct causal relationship with virologic response to TVR-based therapy than HOMA-IR.

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IFN‐α antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling‐3

Cited by 277 publications

References 26 publications

Repression of Interferon Regulatory Factor 1 by Hepatitis C Virus Core Protein Results in Inhibition of Antiviral and Immunomodulatory Genes

Repression of Interferon Regulatory Factor 1 by Hepatitis C Virus Core Protein Results in Inhibition of Antiviral and Immunomodulatory Genes

The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms

Homeostasis model assessment of insulin resistance does not seem to predict response to telaprevir in chronic hepatitis C in the REALIZE trial

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