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Hepatitis C virus kinetics by administration of pegylated interferon-α in human and chimeric mice carrying human hepatocytes with variants of the IL28B gene.

Watanabe T, Sugauchi F, Tanaka Y, Matsuura K, Yatsuhashi H, Murakami S, Iijima S, Iio E, Sugiyama M, Shimada T, Kakuni M, Kohara M, Mizokami M - Gut (2012)

Bottom Line: However, it is unclear whether genetic variations near the IL28B gene influence hepatic interferon (IFN)-stimulated gene (ISG) induction or cellular immune responses, lead to the viral reduction during IFN treatment.There were significant differences in the reduction of HCV-RNA levels after peg-IFN-α plus ribavirin therapy based on the IL28B SNP rs8099917 between TT (favourable) and TG/GG (unfavourable) genotypes in patients; the first-phase viral decline slope per day and second-phase slope per week in TT genotype were significantly higher than in TG/GG genotype.On peg-IFN-α administration to chimeric mice, however, no significant difference in the median reduction of HCV-RNA levels and the induction of antiviral ISG was observed between favourable and unfavourable human hepatocyte genotypes.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

ABSTRACT

Objective: Recent studies have demonstrated that genetic polymorphisms near the IL28B gene are associated with the clinical outcome of pegylated interferon α (peg-IFN-α) plus ribavirin therapy for patients with chronic hepatitis C virus (HCV). However, it is unclear whether genetic variations near the IL28B gene influence hepatic interferon (IFN)-stimulated gene (ISG) induction or cellular immune responses, lead to the viral reduction during IFN treatment.

Design: Changes in HCV-RNA levels before therapy, at day 1 and weeks 1, 2, 4, 8 and 12 after administering peg-IFN-α plus ribavirin were measured in 54 patients infected with HCV genotype 1. Furthermore, we prepared four lines of chimeric mice having four different lots of human hepatocytes containing various single nucleotide polymorphisms (SNP) around the IL28B gene. HCV infecting chimeric mice were subcutaneously administered with peg-IFN-α for 2 weeks.

Results: There were significant differences in the reduction of HCV-RNA levels after peg-IFN-α plus ribavirin therapy based on the IL28B SNP rs8099917 between TT (favourable) and TG/GG (unfavourable) genotypes in patients; the first-phase viral decline slope per day and second-phase slope per week in TT genotype were significantly higher than in TG/GG genotype. On peg-IFN-α administration to chimeric mice, however, no significant difference in the median reduction of HCV-RNA levels and the induction of antiviral ISG was observed between favourable and unfavourable human hepatocyte genotypes.

Conclusions: As chimeric mice have the characteristic of immunodeficiency, the response to peg-IFN-α associated with the variation in IL28B alleles in chronic HCV patients would be composed of the intact immune system.

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Related in: MedlinePlus

Median reduction of hepatitis C virus (HCV)-RNA levels (log copies/ml) after administering pegylated interferon α to chimeric mice having human hepatocytes containing various single nucleotide polymorphisms around the IL28B gene as favourable (rs8099917 TT) and unfavourable (rs8099917 TG) genotypes. Data are represented as mean+SD. Chimeric mice infected with a) serum A (n=7; favourable genotype, n=6; unfavourable genotype), (B) serum B (n=2, each genotype), and (C) serum C (n=2, each genotype). All serum samples were obtained from HCV-1b patients.
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GUTJNL2012302553F4: Median reduction of hepatitis C virus (HCV)-RNA levels (log copies/ml) after administering pegylated interferon α to chimeric mice having human hepatocytes containing various single nucleotide polymorphisms around the IL28B gene as favourable (rs8099917 TT) and unfavourable (rs8099917 TG) genotypes. Data are represented as mean+SD. Chimeric mice infected with a) serum A (n=7; favourable genotype, n=6; unfavourable genotype), (B) serum B (n=2, each genotype), and (C) serum C (n=2, each genotype). All serum samples were obtained from HCV-1b patients.

Mentions: In order to clarify the association between IL28B alleles of human hepatocytes and the response to peg-IFN-α, we prepared four lines of uPA/SCID mice and four different lots of human hepatocytes containing various rs8099917, rs8103142 and rs12979860 SNPs around the IL28B gene (table 2). The chimeric mice were inoculated with serum samples from each HCV-1b patient, and then HCV-RNA levels had increased and reached more than 106 copies/ml in all chimeric mice sera at 2 weeks after inoculation. After confirming the peak of HCV-RNA in all chimeric mice, they were subcutaneously administered with four times injections of the bolus dose of peg-IFN-α2a for 2 weeks (table 3). Figure 4 shows the change in the serum HCV-RNA levels for 14 days during IFN injection into chimeric mice transplanted with IL28B favourable or unfavourable human hepatocyte genotypes. On peg-IFN-α administration, no significant difference in the median reduction in HCV-RNA levels in the serum A-infected22 chimeric mice sera was observed between favourable (n=7) and unfavourable (n=6) IL28B genotypes on days 1, 3, 7 and 14 (−1.2 vs −1.3, −1.4 vs −1.4, −1.8 vs −1.7, and −2.3 vs −1.9 log copies/ml) (figure 4A). Moreover, we prepared two additional serum samples from the other HCV-1b patients (serum B and C)21 to confirm the influence of IL28B genotype in early viral kinetics during IFN treatment. After establishing persistent infection with new HCV-1b strains in all chimeric mice, they were also administered four times injections of the bolus dose of peg-IFN-α2a for 2 weeks (figure 4B,C). In a similar fashion, no significant difference in HCV-RNA reduction in chimeric mice sera was observed between favourable and unfavourable IL28B genotypes.


Hepatitis C virus kinetics by administration of pegylated interferon-α in human and chimeric mice carrying human hepatocytes with variants of the IL28B gene.

Watanabe T, Sugauchi F, Tanaka Y, Matsuura K, Yatsuhashi H, Murakami S, Iijima S, Iio E, Sugiyama M, Shimada T, Kakuni M, Kohara M, Mizokami M - Gut (2012)

Median reduction of hepatitis C virus (HCV)-RNA levels (log copies/ml) after administering pegylated interferon α to chimeric mice having human hepatocytes containing various single nucleotide polymorphisms around the IL28B gene as favourable (rs8099917 TT) and unfavourable (rs8099917 TG) genotypes. Data are represented as mean+SD. Chimeric mice infected with a) serum A (n=7; favourable genotype, n=6; unfavourable genotype), (B) serum B (n=2, each genotype), and (C) serum C (n=2, each genotype). All serum samples were obtained from HCV-1b patients.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756516&req=5

GUTJNL2012302553F4: Median reduction of hepatitis C virus (HCV)-RNA levels (log copies/ml) after administering pegylated interferon α to chimeric mice having human hepatocytes containing various single nucleotide polymorphisms around the IL28B gene as favourable (rs8099917 TT) and unfavourable (rs8099917 TG) genotypes. Data are represented as mean+SD. Chimeric mice infected with a) serum A (n=7; favourable genotype, n=6; unfavourable genotype), (B) serum B (n=2, each genotype), and (C) serum C (n=2, each genotype). All serum samples were obtained from HCV-1b patients.
Mentions: In order to clarify the association between IL28B alleles of human hepatocytes and the response to peg-IFN-α, we prepared four lines of uPA/SCID mice and four different lots of human hepatocytes containing various rs8099917, rs8103142 and rs12979860 SNPs around the IL28B gene (table 2). The chimeric mice were inoculated with serum samples from each HCV-1b patient, and then HCV-RNA levels had increased and reached more than 106 copies/ml in all chimeric mice sera at 2 weeks after inoculation. After confirming the peak of HCV-RNA in all chimeric mice, they were subcutaneously administered with four times injections of the bolus dose of peg-IFN-α2a for 2 weeks (table 3). Figure 4 shows the change in the serum HCV-RNA levels for 14 days during IFN injection into chimeric mice transplanted with IL28B favourable or unfavourable human hepatocyte genotypes. On peg-IFN-α administration, no significant difference in the median reduction in HCV-RNA levels in the serum A-infected22 chimeric mice sera was observed between favourable (n=7) and unfavourable (n=6) IL28B genotypes on days 1, 3, 7 and 14 (−1.2 vs −1.3, −1.4 vs −1.4, −1.8 vs −1.7, and −2.3 vs −1.9 log copies/ml) (figure 4A). Moreover, we prepared two additional serum samples from the other HCV-1b patients (serum B and C)21 to confirm the influence of IL28B genotype in early viral kinetics during IFN treatment. After establishing persistent infection with new HCV-1b strains in all chimeric mice, they were also administered four times injections of the bolus dose of peg-IFN-α2a for 2 weeks (figure 4B,C). In a similar fashion, no significant difference in HCV-RNA reduction in chimeric mice sera was observed between favourable and unfavourable IL28B genotypes.

Bottom Line: However, it is unclear whether genetic variations near the IL28B gene influence hepatic interferon (IFN)-stimulated gene (ISG) induction or cellular immune responses, lead to the viral reduction during IFN treatment.There were significant differences in the reduction of HCV-RNA levels after peg-IFN-α plus ribavirin therapy based on the IL28B SNP rs8099917 between TT (favourable) and TG/GG (unfavourable) genotypes in patients; the first-phase viral decline slope per day and second-phase slope per week in TT genotype were significantly higher than in TG/GG genotype.On peg-IFN-α administration to chimeric mice, however, no significant difference in the median reduction of HCV-RNA levels and the induction of antiviral ISG was observed between favourable and unfavourable human hepatocyte genotypes.

View Article: PubMed Central - PubMed

Affiliation: Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

ABSTRACT

Objective: Recent studies have demonstrated that genetic polymorphisms near the IL28B gene are associated with the clinical outcome of pegylated interferon α (peg-IFN-α) plus ribavirin therapy for patients with chronic hepatitis C virus (HCV). However, it is unclear whether genetic variations near the IL28B gene influence hepatic interferon (IFN)-stimulated gene (ISG) induction or cellular immune responses, lead to the viral reduction during IFN treatment.

Design: Changes in HCV-RNA levels before therapy, at day 1 and weeks 1, 2, 4, 8 and 12 after administering peg-IFN-α plus ribavirin were measured in 54 patients infected with HCV genotype 1. Furthermore, we prepared four lines of chimeric mice having four different lots of human hepatocytes containing various single nucleotide polymorphisms (SNP) around the IL28B gene. HCV infecting chimeric mice were subcutaneously administered with peg-IFN-α for 2 weeks.

Results: There were significant differences in the reduction of HCV-RNA levels after peg-IFN-α plus ribavirin therapy based on the IL28B SNP rs8099917 between TT (favourable) and TG/GG (unfavourable) genotypes in patients; the first-phase viral decline slope per day and second-phase slope per week in TT genotype were significantly higher than in TG/GG genotype. On peg-IFN-α administration to chimeric mice, however, no significant difference in the median reduction of HCV-RNA levels and the induction of antiviral ISG was observed between favourable and unfavourable human hepatocyte genotypes.

Conclusions: As chimeric mice have the characteristic of immunodeficiency, the response to peg-IFN-α associated with the variation in IL28B alleles in chronic HCV patients would be composed of the intact immune system.

Show MeSH
Related in: MedlinePlus