Variants in IL28B in Liver Recipients and Donors Correlate With Response to Peg-Interferon and Ribavirin Therapy for Recurrent Hepatitis C

Fukuhara, Takasuke; Taketomi, Akinobu; Mizutani, Takashi; Okano, Shinji; Ninomiya, Ai; Abe, Takayuki; Uchiyama, Hideaki; Soejima, Yuji; Shirabe, Ken; Matsuura, Yoshiharu; Maehara, Yoshihiko

doi:10.1053/j.gastro.2010.07.058

Cited by 198 publications

(147 citation statements)

References 36 publications

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“…The IL28B genotype is associated with the sensitivity of IFN treatment for chronic hepatitis C patients (79)(80)(81), and patients with the minor IL28B genotype exhibit lower susceptibility to the treatment than those with major genotypes. Although FU97 cells showed lower sensitivity to the IFN-␣ treatment than Huh7 cells, FU97 and Huh7 cells possess major and minor IL28B genotypes , and FU97 cured 7-1 cells were infected with HCVcc/JFH-2 at an MOI of 1, and infectious titers in the culture supernatants were determined by focus-forming assay.…”

Section: Discussionmentioning

confidence: 99%

Novel Permissive Cell Lines for Complete Propagation of Hepatitis C Virus

Mai

Fukuhara

Ono

et al. 2014

J Virol

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Hepatitis C virus (HCV) is a major etiologic agent of chronic liver diseases. Although the HCV life cycle has been clarified by studying laboratory strains of HCV derived from the genotype 2a JFH-1 strain (cell culture-adapted HCV [HCVcc]), the mechanisms of particle formation have not been elucidated. Recently, we showed that exogenous expression of a liver-specific microRNA, miR-122, in nonhepatic cell lines facilitates efficient replication but not particle production of HCVcc, suggesting that liver-specific host factors are required for infectious particle formation. In this study, we screened human cancer cell lines for expression of the liver-specific ␣-fetoprotein by using a cDNA array database and identified liver-derived JHH-4 cells and stomach-derived FU97 cells, which express liver-specific host factors comparable to Huh7 cells. These cell lines permit not only replication of HCV RNA but also particle formation upon infection with HCVcc, suggesting that hepatic differentiation participates in the expression of liver-specific host factors required for HCV propagation. HCV inhibitors targeting host and viral factors exhibited different antiviral efficacies between Huh7 and FU97 cells. Furthermore, FU97 cells exhibited higher susceptibility for propagation of HCVcc derived from the JFH-2 strain than Huh7 cells. These results suggest that hepatic differentiation participates in the expression of liver-specific host factors required for complete propagation of HCV. IMPORTANCEPrevious studies have shown that liver-specific host factors are required for efficient replication of HCV RNA and formation of infectious particles. In this study, we screened human cancer cell lines for expression of the liver-specific ␣-fetoprotein by using a cDNA array database and identified novel permissive cell lines for complete propagation of HCVcc without any artificial manipulation. In particular, gastric cancer-derived FU97 cells exhibited a much higher susceptibility to HCVcc/JFH-2 infection than observed in Huh7 cells, suggesting that FU97 cells would be useful for further investigation of the HCV life cycle, as well as the development of therapeutic agents for chronic hepatitis C. More than 170 million individuals worldwide are infected with hepatitis C virus (HCV), and the cirrhosis and hepatocellular carcinoma induced by HCV infection are life-threatening diseases (1). Current standard therapy combining pegylated-interferon (peg-IFN) and ribavirin (RBV) has achieved a sustained virological response (SVR) in 50% of individuals infected with HCV genotype 1 (2). Recently, directly acting antiviral (DAA) agents have been applied in a clinical setting (3). An SVR rate of over 80% has been realized by combination therapy with peg-IFN, RBV, and NS3/4A inhibitors in genotype 1 patients (4, 5). In addition, several DAAs, including inhibitors for NS3/4A protease, NS5A, and NS5B polymerase, are currently in clinical trials. Several reports have shown that in vitro replication of HCV RNA is significantly inhibited by treat...

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Section: Discussionmentioning

confidence: 99%

Novel Permissive Cell Lines for Complete Propagation of Hepatitis C Virus

Mai

Fukuhara

Ono

et al. 2014

J Virol

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“…25 SVR was significantly higher in recipients carrying the major homozygous allele than in those with the minor heterozygous or homozygous allele (54% vs 11%; P < 0.003) ( Table 2). SVR was also significantly higher in recipients transplanted with liver grafts from donors carrying the major homozygote (44% vs 9%; P < 0.025).…”

Section: Il-28b Variation and The Association With Response To Hcv Anmentioning

confidence: 99%

Discovery of critical host factor, IL‐28B, associated with response to hepatitis C virus treatment

Mizokami

2012

J of Gastro and Hepatol

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Chronic hepatitis C affects 2.2-3.0% of the world population (130 million-170 million). Pegylated interferon-a (PEG-IFN-a) in combination with ribavirin (RBV), the approved and standard therapy, leads to viral eradication in about 50% of treated patients. In 2009, genome-wide association studies (GWAS) identified host genetic variation to be critical for predicting treatment response and spontaneous clearance in patients infected with hepatitis C virus (HCV). A correlated set of polymorphisms in the region of the interleukin-28B (IL-28B) gene on chromosome 19, coding for interferon (IFN)-l3 were associated with clearance of genotype 1 hepatitis C virus (HCV) in patients treated with PEG-IFN-a and RBV. The same polymorphisms were subsequently associated with spontaneous clearance of HCV in untreated patients. In addition, prediction of viral response to PEG-IFN-a and RBV therapy of patients with recurrent HCV infection after orthotopic liver transplantation depends on the IL-28B genotype of both recipient and donor tissues. Diagnosis of a patient's IL-28B genotype is likely to aid in clinical decision making with standard-of-care regimens. Future studies will investigate the possibility of individualizing treatment duration and novel regimens according to IL-28B genotype. As GWAS yield unexpected data, this approach could lead to the development of novel drug therapy, such as already appears promising with IFN-l. In this Okuda lecture, I present the current understanding in regard to the relationship between host variations and clinical outcome of hepatitis C.

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“…However, many patients cannot tolerate curative doses or do not respond to therapy [93][94][95]. Therefore, as it would be ideal to be able to predict which patients would benefit from PEG-IFN plus RBV therapy for recurrent HCV, it was recently reported that variants of the SNPs in or around the IL-28B gene from liver donors are also strongly associated to the degree of graft inflammation and the response to therapy of HCV-infected liver recipients [96][97][98].…”

Section: Molecular Epidemiology Of Hcv-relatedmentioning

confidence: 99%

Evolving Trends in the Hepatitis C Virus Molecular Epidemiology Studies: From the Viral Sequences to the Human Genome

Trinks

Gadano

Argibay

2012

Epidemiology Research International

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Hepatitis C virus (HCV) represents a major worldwide public health problem. The search for the key molecular biomarkers that may provide insight on the basis of the differences in disease progression, severity, and response to therapy is crucial for understanding the natural history of HCV, for estimating the burden of infection and for developing preventive interventions. Initially, molecular epidemiology studies have focused on studying the viral genetic diversity (genotypes, genetic variants, specific nucleotide and amino acid substitutions). However, the clinical heterogeneities of HCV infection and the imperfect predictability of the response to treatment have suggested the need to search for host genetic biomarkers. This led to the discovery of genetic polymorphisms playing a major role in the evolution of infection, as well as in treatment response and adverse effects, such asIL-28B,ITPA, andIP-10. As a consequence, nowadays the focus of molecular epidemiology studies has turned from the viral to the human genome. This paper will cover recent reports on the subject describing the most relevant viral as well as host genetic risk factors analyzed by past and current HCV molecular epidemiology studies.

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Variants in IL28B in Liver Recipients and Donors Correlate With Response to Peg-Interferon and Ribavirin Therapy for Recurrent Hepatitis C

Cited by 198 publications

References 36 publications

Novel Permissive Cell Lines for Complete Propagation of Hepatitis C Virus

Novel Permissive Cell Lines for Complete Propagation of Hepatitis C Virus

Discovery of critical host factor, IL‐28B, associated with response to hepatitis C virus treatment

Evolving Trends in the Hepatitis C Virus Molecular Epidemiology Studies: From the Viral Sequences to the Human Genome

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