Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C

Asselah, Tarik; Bièche, Ivan; Narguet, Stéphanie; Sabbagh, Audrey; Laurendeau, Ingrid; Ripault, Marie–Pierre; Boyer, Nathalie; Martinot‐Peignoux, Michèle; Valla, Dominique; Vidaud, Michel; Marcellin, Patrick

doi:10.1136/gut.2007.128611

Cited by 196 publications

(193 citation statements)

References 37 publications

(36 reference statements)

Supporting

Mentioning

166

Contrasting

Unclassified

Order By: Relevance

“…ISG15 is one of the most abundant ISGs induced after virus infection and type I IFN treatment, and we and others have found that increased pre-treatment ISG15 expression in the livers of HCV-infected patients predicts subsequent treatment failure (Chen et al, 2005;Feld et al, 2007;Asahina et al, 2008;Asselah et al, 2008;Sarasin-Filipowicz et al, 2008). Although ISG15 is generally considered to be antiviral, we have presented evidence here that ISGylation promotes HCV production, decreases the anti-HCV effect of IFN-a and is particularly relevant for steps downstream of HCV RNA replication.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

ISG15, a ubiquitin-like interferon-stimulated gene, promotes hepatitis C virus production in vitro: implications for chronic infection and response to treatment

Chen

Sun

Meng

et al. 2009

Journal of General Virology

View full text Add to dashboard Cite

Upregulation of interferon (IFN)-stimulated genes (ISGs), including IFN-stimulated gene 15 (ISG15) and other members of the ISG15 pathway, in pre-treatment liver tissue of patients chronically infected with hepatitis C virus (HCV) is associated with subsequent treatment failure (pegylated IFN-a/ribavirin). This study assessed the effect of ISG15 on HCV production in vitro. The levels of ISG15 and of its conjugation to target proteins (ISGylation) were increased by plasmid transfection, but ISGylation was inhibited by small interfering RNA directed against the E1 activating enzyme, Ube1L, in Huh7.5 cells. Cells were infected with HCV FL-J6/JFH virus, and HCV RNA and viral titres were determined. Levels of both HCV RNA and virus increased when levels of ISG15 and ISGylation were increased, and decreased when ISGylation was inhibited. The effects of ISGylation on HCV were independent of upstream IFN signalling: IFN-a-induced ISG expression was not altered by Ube1L knockdown. Thus, although ISG15 has antiviral activity against most viruses, ISG15 promotes HCV production. HCV might exploit ISG15 as a host immune evasion mechanism, and this may in part explain how increased expression of ISGs, especially ISG15, correlates with subsequent IFN-based treatment failure. INTRODUCTIONHepatitis C virus (HCV) is adept at evading host antiviral mechanisms and is often resistant to the current standard of care -combination treatment with pegylated interferon (IFN)-a and ribavirin (PegIFN/Rib). This regimen eradicates the virus in only 50 % of cases. A number of mechanisms contribute to evasion and treatment resistance, including cleavage of the RIG-I adaptor protein IPS1/ MAVS/Cardif by the HCV NS3/NS4A protease and modulation of the host response by the HCV core protein Loo et al., 2006). However, none of these mechanisms has consistently been demonstrated to play a role in the clinical disease and thus cannot explain the ability of the virus to escape the host response in patients.Response to treatment can be predicted by levels of expression of IFN-stimulated genes (ISGs) in the liver prior to initiation of PegIFN/Rib treatment. Non-responders have increased expression of a number of ISGs (Chen et al., 2005;Feld et al., 2007; Asahina et al., 2008;Asselah et al., 2008;Sarasin-Filipowicz, et al., 2008). Three of these ISGs are components of the ISG15 ubiquitin-like pathway. ISG15 was the first ubiquitin-like protein to be described and, like its homologue ubiquitin, is conjugated to proteins in a tightly regulated process called ISGylation. The ISG15 E1 activating protein, Ube1L, coordinates with the E2 conjugating enzyme (UbcH8) and the E3 ligase (CEB1) to join the C terminus of ISG15 to a wide variety of proteins (Loeb & Haas, 1992). ISG15 can be removed from its target proteins by USP18, an ISG15 protease (Kim et al., 2008b). Thus, ISG15 inhibits virus production for many viruses, but may promote production of some.In this study, we examined the role of ISG15 and ISGylation in HCV production in vitro, using the FL-J6/JFH...

show abstract

Section: Discussionmentioning

confidence: 99%

“…Non-responders have increased expression of a number of ISGs (Chen et al, 2005;Feld et al, 2007; Asahina et al, 2008;Asselah et al, 2008;Sarasin-Filipowicz, et al, 2008). Three of these ISGs are components of the ISG15 ubiquitin-like pathway.…”

Section: Introductionmentioning

confidence: 99%

ISG15, a ubiquitin-like interferon-stimulated gene, promotes hepatitis C virus production in vitro: implications for chronic infection and response to treatment

Chen

Sun

Meng

et al. 2009

Journal of General Virology

View full text Add to dashboard Cite

show abstract

“…20 Analysis of hepatic gene expression demonstrated that the up-regulation of ISGs in the liver before treatment may be related to a poor treatment response. [6][7][8][9] To reveal the underlying mechanism of treatment resistance, two reports compared gene expression profiling in the liver before and during therapy, and showed that patients with up-regulated ISGs in the liver prior to treatment failed to further induce ISGs following the administration of IFN and could not eliminate HCV. 6,7 We performed a similar analysis and observed that these findings were more evident in liver lobular cells than in infiltrating lymphocytes in the portal area (submitted for publication).…”

Section: Discussionmentioning

confidence: 99%

“…6,7 Interferon-stimulated genes (ISGs) upregulated in the liver prior to treatment might be related to the poor induction of ISGs and the impaired eradication of HCV during treatment. [6][7][8][9] This may be because the ISGs have already been maximally induced before treatment. However, the clinical relevance of the expression of ISGs as predictive factors for the outcome of treatment has not yet been fully evaluated.…”

Section: Introductionmentioning

confidence: 99%

Hepatic ISG Expression Is Associated With Genetic Variation in Interleukin 28B and the Outcome of IFN Therapy for Chronic Hepatitis C

et al. 2010

View full text Add to dashboard Cite

“…The local type I IFN response induced by HCV seems to be paradox, as these interferons can inhibit HCV replication. In addition, patients that are non-responders to IFN-based therapies have highly elevated expression levels of a subset of ISGs compared to patients who cleared the virus (Asselah et al 2008;Chen et al 2005). ISG15, an ubiquitin-like modifier, is one of these genes.…”

Section: Interferon Response; Friend or Foe?mentioning

confidence: 99%

Toll Like Receptors in Chronic Viral Hepatitis – Friend and Foe

Broering¹,

Lu²,

Schlaak³

2011

Viral Hepatitis - Selected Issues of Pathogenesis and Diagnostics

View full text Add to dashboard Cite

Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C

Cited by 196 publications

References 37 publications

ISG15, a ubiquitin-like interferon-stimulated gene, promotes hepatitis C virus production in vitro: implications for chronic infection and response to treatment

ISG15, a ubiquitin-like interferon-stimulated gene, promotes hepatitis C virus production in vitro: implications for chronic infection and response to treatment

Hepatic ISG Expression Is Associated With Genetic Variation in Interleukin 28B and the Outcome of IFN Therapy for Chronic Hepatitis C

Toll Like Receptors in Chronic Viral Hepatitis – Friend and Foe

Contact Info

Product

Resources

About