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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

(A) The first-phase viral decline slope per day (Ph1/day) and (B) second-phase viral decline slope per week (Ph2/week) in hepatitis C virus (HCV) genotype 1-infected patients treated with pegylated interferon α plus ribavirin. The lines across the boxes indicate the median values. The hash marks above and below the boxes indicate the 90th and 10th percentiles for each group, respectively.
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GUTJNL2012302553F3: (A) The first-phase viral decline slope per day (Ph1/day) and (B) second-phase viral decline slope per week (Ph2/week) in hepatitis C virus (HCV) genotype 1-infected patients treated with pegylated interferon α plus ribavirin. The lines across the boxes indicate the median values. The hash marks above and below the boxes indicate the 90th and 10th percentiles for each group, respectively.

Mentions: Figure 1 shows the initial change in the serum HCV-RNA level for 14 days after peg-IFN-α plus ribavirin therapy in patients infected with HCV genotype 1 based on the genetic polymorphism near the IL28B gene. The immediate antiviral response (viral drop 24 h after the first IFN injection) was significantly higher in HCV patients with genotype TT than genotype TG/GG (−1.08 vs −0.39 log IU/ml, p<0.001). Figure 2 also shows the subsequent change in the serum HCV-RNA reduction after peg-IFN-α plus ribavirin therapy in patients infected with HCV genotype 1. Similarly, during peg-IFN-α plus ribavirin therapy, a statistically significant difference in the median reduction in serum HCV-RNA levels was noted according to the genotype (TT vs TG/GG). The median reduction in the serum HCV-RNA levels (log IU/ml) at 1, 2, 4, 8 and 12 weeks between genotypes TT and TG/GG was as follows: −1.58 vs −0.62, p<0.001; −2.35 vs −0.91, p<0.001; −3.48 vs −1.56, p<0.001; −4.53 vs −2.37, p<0.01; −4.93 vs −2.86, p<0.001. Furthermore, the initial first-phase viral decline slope per day (Ph1/day) and subsequent second-phase viral decline slope per week (Ph2/week) in TT genotype were significantly higher than in genotype TG/GG (Ph1/day 0.94±0.83 vs 0.38±0.40 log IU/ml, p<0.001; Ph2/week 0.08±0.06 vs 0.04±0.03 log IU/ml, p<0.001) (figure 3).


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)

(A) The first-phase viral decline slope per day (Ph1/day) and (B) second-phase viral decline slope per week (Ph2/week) in hepatitis C virus (HCV) genotype 1-infected patients treated with pegylated interferon α plus ribavirin. The lines across the boxes indicate the median values. The hash marks above and below the boxes indicate the 90th and 10th percentiles for each group, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

GUTJNL2012302553F3: (A) The first-phase viral decline slope per day (Ph1/day) and (B) second-phase viral decline slope per week (Ph2/week) in hepatitis C virus (HCV) genotype 1-infected patients treated with pegylated interferon α plus ribavirin. The lines across the boxes indicate the median values. The hash marks above and below the boxes indicate the 90th and 10th percentiles for each group, respectively.
Mentions: Figure 1 shows the initial change in the serum HCV-RNA level for 14 days after peg-IFN-α plus ribavirin therapy in patients infected with HCV genotype 1 based on the genetic polymorphism near the IL28B gene. The immediate antiviral response (viral drop 24 h after the first IFN injection) was significantly higher in HCV patients with genotype TT than genotype TG/GG (−1.08 vs −0.39 log IU/ml, p<0.001). Figure 2 also shows the subsequent change in the serum HCV-RNA reduction after peg-IFN-α plus ribavirin therapy in patients infected with HCV genotype 1. Similarly, during peg-IFN-α plus ribavirin therapy, a statistically significant difference in the median reduction in serum HCV-RNA levels was noted according to the genotype (TT vs TG/GG). The median reduction in the serum HCV-RNA levels (log IU/ml) at 1, 2, 4, 8 and 12 weeks between genotypes TT and TG/GG was as follows: −1.58 vs −0.62, p<0.001; −2.35 vs −0.91, p<0.001; −3.48 vs −1.56, p<0.001; −4.53 vs −2.37, p<0.01; −4.93 vs −2.86, p<0.001. Furthermore, the initial first-phase viral decline slope per day (Ph1/day) and subsequent second-phase viral decline slope per week (Ph2/week) in TT genotype were significantly higher than in genotype TG/GG (Ph1/day 0.94±0.83 vs 0.38±0.40 log IU/ml, p<0.001; Ph2/week 0.08±0.06 vs 0.04±0.03 log IU/ml, p<0.001) (figure 3).

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