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

Honda, Masao; Sakai, Akito; Yamashita, Tatsuya; Nakamoto, Yasunari; Mizukoshi, Eishiro; Sakai, Yoshio; Nakamura, Mikiko; Shirasaki, Takayoshi; Horimoto, Katsuhisa; Tanaka, Yasuhito; Tokunaga, Katsushi; Mizokami, Masashi

doi:10.1053/j.gastro.2010.04.049

Cited by 368 publications

(418 citation statements)

References 22 publications

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“…4,5 However, in the SNP expression database http://humangenome.duke.edu/software, no difference in peripheral blood mononuclear cell expression of IL28B on the basis of rs12979860 genotype has been noted. In addition, in two independent studies, 22,23 no differences in levels of intrahepatic IL28B gene expression on the basis of IL28B genotype were observed. Further studies are needed to elucidate the causal variants and the biological mechanisms underlying the association between IL28B genotype and HCV treatment response.…”

Section: Mechanisms Of Action Of Lambda Ifns and Role Of Il28bmentioning

confidence: 88%

“…In one study, gene expression profiles were analyzed in liver tissue from 91 patients with chronic hepatitis C who received PEG-IFN and RBV combination therapy. 22 Genetic variation in host rs8099917 was determined, and the expression of ISGs was evaluated in all samples. Hepatic ISGs were associated with the IL28B polymorphism (OR 18.1; P < 0.001), and their expression was significantly higher in patients with the minor genotypes (T/G or G/G), which were associated with nonresponse to treatment, than in those with the major genotype (T/T).…”

Section: Mechanisms Of Action Of Lambda Ifns and Role Of Il28bmentioning

confidence: 99%

See 1 more Smart Citation

Hepatitis C pharmacogenetics: State of the art in 2010

Afdhal¹,

McHutchison²,

Zeuzem³

et al. 2011

Hepatology

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131

104

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In 2009, a correlated set of polymorphisms in the region of the interleukin-28B (IL28B) gene were associated with clearance of genotype 1 hepatitis C virus (HCV) in patients treated with pegylated interferon-alfa and ribavirin. The same polymorphisms were subsequently associated with spontaneous clearance of HCV in untreated patients. The link between IL28B genotype and HCV clearance may impact decisions regarding initiation of current therapy, the design and interpretation of clinical studies, the economics of treatment, and the process of regulatory approval for new anti-HCV therapeutic agents. (HEPATOLOGY 2011;53:336-345)

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Section: Mechanisms Of Action Of Lambda Ifns and Role Of Il28bmentioning

confidence: 88%

Section: Mechanisms Of Action Of Lambda Ifns and Role Of Il28bmentioning

confidence: 99%

Hepatitis C pharmacogenetics: State of the art in 2010

Afdhal¹,

McHutchison²,

Zeuzem³

et al. 2011

Hepatology

Self Cite

131

104

View full text Add to dashboard Cite

show abstract

“…Results from many previous studies have indicated that there is an association between IL28b SNPs and high pre-treatment levels of hepatic ISG (Honda et al, 2010;Lau et al, 2013;Sarasin-Filipowicz et al, 2008). In this scenario, the presence of IFN-l4 may result in the persistent stimulation of ISGs, including many negative regulators in the IFN pathway, ultimately leading to a poor response to type I interferon therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Patients carrying favourable alleles usually have an approximately two fold higher rate of sustained virological response (SVR) compared with those carrying unfavourable alleles or heterozygotes (Suppiah et al, 2009). Although the specific molecular basis underlying the SNP function has not yet been elucidated, the association between the genetic variants and their responses to therapy suggests that IFN-ls may play an important role in HCV pathogenesis (Honda et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

IFN-λ4 desensitizes the response to IFN-α treatment in chronic hepatitis C through long-term induction of USP18

Fan

Xie

Zhao

et al. 2016

Journal of General Virology

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The recently discovered interferon lambda 4 (IFN-l4) is a new member of the human type III interferons which could induce a strong antiviral effect through the JAK-STAT cascade. However, hepatitis C virus (HCV) patients who are capable of expressing IFN-l4 usually have poor response to IFN-a treatment, and the mechanism behind this paradox remains unknown. Here, we reported that IFN-l4 desensitized IFN-a-stimulated JAK-STAT signalling. Microarray analysis revealed that IFN-l4 could induce ubiquitin specific peptidase 18 (USP18), a known inhibitor of the type I IFN signalling pathway, in a more sustained pattern compared with type I interferon induction. Moreover, only HCV genotype 1b but not 2a replicon cells pretreated with IFN-l4 had an attenuated response to type I IFN treatment, which might be due to the different level of USP18 expression. Consistently, knockdown of USP18 in HCV genotype 1b-containing replicon cells reversed the resistance induced by IFN-l4 and promoted viral clearance. Finally, IFN-l4 is also strongly associated with the poor response to IFN-a in a Chinese HCV genotype 1b cohort. In conclusion, these data indicate that IFN-l4 attenuates the response of HCV genotype 1b to IFN-a therapy and inhibits the JAK-STAT signalling pathway by inducing USP18 expression.

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“…The mechanism by which these genetic variants influence the outcome of HCV infection, i.e., whether they influence IFN-k3 expression by affecting gene transcription or are linked to a coding variant (Lys70Arg) of the IFN-k3 protein, is still debated [14,18]. However, it is known that these variants result in a different pattern of activation of the innate immune system against HCV infection, as determined by the different basal and IFN-a induced expression of interferon-stimulated genes and inflammatory activity [21,22]. Favorable IL28B variants, likely through the effect of inflammatory cytokines on lipid metabolism [23], protect against the development of steatosis [24] and possibly steatosis-associated fibrosis progression and increased HCC risk [2,4].…”

mentioning

confidence: 99%

IL28B, HCV core mutations, and hepatocellular carcinoma: does host genetic make-up shape viral evolution in response to immunity?

2011

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Mutations in the core sequence of the HCV genome have been reported to influence treatment response, fibrosis progression, and hepatocarcinogenesis in Asian patients with genotype-1 chronic hepatitis C (CHC). In this issue, Miura et al. report data consistent with a causal relationship between the R70 ? Q70 core variant and hepatocellular carcinoma (HCC) risk in CHC genotype-1b patients, by the prospective evaluation of changes in the consensus sequence in the entire open reading frame between treatment failure and HCC development or end of follow-up, and validation of the initial findings in a confirmatory cohort. Furthermore, they observed an association between the IL28B genotype, which is believed to influence the immune response to viral infection, and the direction of time-dependent changes in core residue 70, with unfavorable IL28B genotypes linked to a preferential shift to the 70Q associated with HCC. Although this association needs to be validated in independent cohorts, and IL28B variants did not influence HCC risk, these results suggest that IL28B genotype might not only influence the behavior of the innate immune system in the presence of HCV genotype-1 infection but also shape the resultant viral evolution, with possible consequences on major clinical outcomes, such as HCC development, and treatment response.

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

Cited by 368 publications

References 22 publications

Hepatitis C pharmacogenetics: State of the art in 2010

Hepatitis C pharmacogenetics: State of the art in 2010

IFN-λ4 desensitizes the response to IFN-α treatment in chronic hepatitis C through long-term induction of USP18

IL28B, HCV core mutations, and hepatocellular carcinoma: does host genetic make-up shape viral evolution in response to immunity?

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