Journal Mobile Options
Table of Contents
Vol. 53, No. 2, 2010
Issue release date: February 2010
Free Access
Intervirology 2010;53:105–110
(DOI:10.1159/000264200)

Interferon Alpha Receptor 2 Expression by Peripheral Blood Monocytes in Patients with a High Viral Load of Hepatitis C Virus Genotype 1 Showing Substitution of Amino Acid 70 in the Core Region

Ishii K.a · Shinohara M.a · Sawa M.a · Kogame M.a · Higami K.a · Sano M.b · Morita T.b · Sumino Y.a
aDepartment of Internal Medicine, Division of Gastroenterology and Hepatology, and bDepartment of Laboratory Medicine, Toho University School of Medicine, Faculty of Medicine, Tokyo, Japan
email Corresponding Author

Abstract

Background/Aim: When patients with chronic hepatitis C (CHC) are treated with interferon (IFN)-based therapy, achieving serum HCV-RNA negativity by week 12 (early viral response, EVR) is an important predictor of a sustained virologic response. The aim of this study was to clarify whether changes in IFN-α receptor 2 (IFNAR-2) expression by peripheral blood monocytes (Mo) and the EVR rate differed between patients with genotype 1b and a high viral load showing substitution of amino acid 70 in the core region of HCV (mutant, n = 20) and patients without this substitution (wild, n = 23). Patients and Methods: Forty-three CHC patients were studied, and received pegylated IFN plus ribavirin. IFNAR-2 expression by Mo was determined using flow cytometry to measure the mean fluorescence intensity (MFI) before and up to 28 days after starting therapy. Results: The EVR rate of the mutant group was significantly lower than that of the wild group (35 vs.70%). The MFI of Mo was significantly higher in the wild group than in the mutant group before and also 3, 7, and 28 days after starting therapy. Conclusions: Mutation of HCV was related to lower IFNAR-2 expression by Mo before and after starting therapy.


 goto top of outline Key Words

  • Chronic hepatitis C
  • Amino acid substitution
  • Core region
  • Interferon-α receptor 2
  • Peripheral blood leukocyte

 goto top of outline Abstract

Background/Aim: When patients with chronic hepatitis C (CHC) are treated with interferon (IFN)-based therapy, achieving serum HCV-RNA negativity by week 12 (early viral response, EVR) is an important predictor of a sustained virologic response. The aim of this study was to clarify whether changes in IFN-α receptor 2 (IFNAR-2) expression by peripheral blood monocytes (Mo) and the EVR rate differed between patients with genotype 1b and a high viral load showing substitution of amino acid 70 in the core region of HCV (mutant, n = 20) and patients without this substitution (wild, n = 23). Patients and Methods: Forty-three CHC patients were studied, and received pegylated IFN plus ribavirin. IFNAR-2 expression by Mo was determined using flow cytometry to measure the mean fluorescence intensity (MFI) before and up to 28 days after starting therapy. Results: The EVR rate of the mutant group was significantly lower than that of the wild group (35 vs.70%). The MFI of Mo was significantly higher in the wild group than in the mutant group before and also 3, 7, and 28 days after starting therapy. Conclusions: Mutation of HCV was related to lower IFNAR-2 expression by Mo before and after starting therapy.

Copyright © 2009 S. Karger AG, Basel


 goto top of outline References
  1. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358:958–965.
  2. Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J: Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003;38:645–652.
  3. Ferenci P, Fried MW, Shiffman ML, Smith CI, Marinos G, Gonçales FL Jr, Häussinger D, Diago M, Carosi G, Dhumeaux D, Craxì A, Chaneac M, Reddy KR: Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin. Hepatology 2005;43:425–433.
  4. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K, Kumada H: Predictors of viral kinetics to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b. J Med Virol 2007;79:1686–1695.
  5. Akuta N, Suzuki F, Sezaki H, Suzuki Y, Hosaka T, Someya T, Kobayashi M, Saitoh S, Watahiki S, Sato J, Matsuda M, Kobayashi M, Arase Y, Ikeda K, Kumada H: Association of amino acid substitution pattern in core protein of hepatitis C virus genotype 1b high viral load and non-virological response to interferon-ribavirin combination therapy. Intervirology 2005;48:372–380.
  6. Lin W, Kim SS, Yeung E, Kamegaya Y, Blackard JT, Kim KA, Holtzman MJ, Chung RT: Hepatitis C virus core protein blocks interferon signaling by interaction with STAT1 SH2 domain. J Med Virol 2006;80:9226–9235.
  7. Ciccaglione AR, Stellacci E, Marcantonio C, Muto V, Equestre M, Marsili G, Rapicetta M, Battistini A: Repression of interferon regulatory 1 by hepatitis C virus core protein results in inhibition of antiviral and immunomodulatory genes. J Med Virol 2007;81:202–214.
  8. Chen X, Bhandari R, Vinkemeier U, Van Den Akker F, Darnell JE Jr, Kuriyan J: A reinterpretation of the dimerization interface of the N-terminal domains of STATs. Protein Sci 2003;12:361–365.
  9. Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW: Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 2002;285:1–24.
  10. ten Hoeve J, de Jesus Ibarra-Sanchez M, Fu Y, Zhu W, Tremblay M, David M, Shuai K: Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol Cell Biol 2002;22:5662–5668.
  11. Novick D, Cohen B, Rubinstein M: The human interferon alpha/beta receptor: characterization and molecular cloning. Cell 1994;77:391–400.
  12. Domanski P, Witte M, Kellum M, Rubinstein M, Hackett R, Pitha P, Colamonici OP: Cloning and expression of a long form of the beta subunit of the interferon alpha beta receptor that is required for signaling. J Biol Chem 1995;270:21606–20611.
  13. Mizukoshi E, Kaneko S, Yanagi M, Ohno H, Kaji K, Terasaki S, Shimoda A, Matsushita E, Kobayashi K: Expression of interferon alpha/beta receptor in the liver of chronic hepatitis C patients. J Med Virol 1998;56:217–223.
  14. Yatsuhashi H, Fujino T, Matsumoto T, Inoue O, Koga M, Yano M: Immunohistochemical analysis of hepatic interferon alpha-beta receptor level: relationship between receptor expression and response to interferon therapy in patients with chronic hepatitis C. J Hepatol 1999;30:995–1003.
  15. Mathai J, Shimoda K, Banner BF, Mori M, Bonkovsky HL, Barnard GF: IFN alpha-receptor mRNA expression in a United States sample with predominantly genotype 1a/I chronic hepatitis C liver biopsies correlates with response to IFN therapy. J Interferon Cytokine Res 1999;19:1011–1018.
  16. Morita K, Tanaka K, Saito S, Kitamura T, Kiba T, Fujii T, Numata K, Sekihara H: Expression of interferon receptor genes in the liver as a predictor of interferon response in patients with chronic hepatitis C. J Med Virol 1999;58:359–365.
  17. Yamaguchi Y, Hino K, Fujiwara D, Ren F, Katoh Y, Okita K: Expression of type I interferon receptor in liver and peripheral blood mononuclear cells in chronic hepatitis C patients. Dig Dis Sci 2002;47:1611–1617.
  18. Tochizawa S, Akamatsu S, Sugiyama Y, Muraguchi M, Ohmoto Y, Ono Y, Ishikawa H, Tanigami A, Sumida T, Mori T: A flow cytometric method for determination of the interferon receptor IFNAR-2 subsets in peripheral blood leukocyte subsets. J Pharmacol Toxicol Method 2004;50:59–66.
  19. Ren F, Hino K, Yamaguchi Y, Okazaki M, Kitase A, Satoh Y, Korenaga M, Okuda M, Okita K: Hepatitis C virus infection upregulates expression of the type I interferon receptor in human peripheral blood mononuclear cells. Hepatol Res 2003;26:15–22.
  20. Knodell RG, Ishak KG, Black WC, Chen TS, Craig R,Kaplowitz N, Kiernan TW, Wollman J: Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic hepatitis. Hepatology 1981;1:431–435.
  21. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ: Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994;19:1513–1520.

 goto top of outline Author Contacts

Koji Ishii, MD
Department of Internal Medicine, Division of Gastroenterology and Hepatology
6-11-1 Omorinishi, Otaku
Tokyo 143 (Japan)
Tel. +81 3 3762 4151, Fax +81 3 3763 8542, E-Mail iskoji377@med.toho-u.ac.jp


 goto top of outline Article Information

Received: August 5, 2009
Accepted after revision: October 12, 2009
Published online: December 3, 2009
Number of Print Pages : 6
Number of Figures : 3, Number of Tables : 1, Number of References : 21


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 53, No. 2, Year 2010 (Cover Date: February 2010)

Journal Editor: Liebert U.G. (Leipzig)
ISSN: 0300-5526 (Print), eISSN: 1423-0100 (Online)

For additional information: http://www.karger.com/INT


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background/Aim: When patients with chronic hepatitis C (CHC) are treated with interferon (IFN)-based therapy, achieving serum HCV-RNA negativity by week 12 (early viral response, EVR) is an important predictor of a sustained virologic response. The aim of this study was to clarify whether changes in IFN-α receptor 2 (IFNAR-2) expression by peripheral blood monocytes (Mo) and the EVR rate differed between patients with genotype 1b and a high viral load showing substitution of amino acid 70 in the core region of HCV (mutant, n = 20) and patients without this substitution (wild, n = 23). Patients and Methods: Forty-three CHC patients were studied, and received pegylated IFN plus ribavirin. IFNAR-2 expression by Mo was determined using flow cytometry to measure the mean fluorescence intensity (MFI) before and up to 28 days after starting therapy. Results: The EVR rate of the mutant group was significantly lower than that of the wild group (35 vs.70%). The MFI of Mo was significantly higher in the wild group than in the mutant group before and also 3, 7, and 28 days after starting therapy. Conclusions: Mutation of HCV was related to lower IFNAR-2 expression by Mo before and after starting therapy.



 goto top of outline Author Contacts

Koji Ishii, MD
Department of Internal Medicine, Division of Gastroenterology and Hepatology
6-11-1 Omorinishi, Otaku
Tokyo 143 (Japan)
Tel. +81 3 3762 4151, Fax +81 3 3763 8542, E-Mail iskoji377@med.toho-u.ac.jp


 goto top of outline Article Information

Received: August 5, 2009
Accepted after revision: October 12, 2009
Published online: December 3, 2009
Number of Print Pages : 6
Number of Figures : 3, Number of Tables : 1, Number of References : 21


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 53, No. 2, Year 2010 (Cover Date: February 2010)

Journal Editor: Liebert U.G. (Leipzig)
ISSN: 0300-5526 (Print), eISSN: 1423-0100 (Online)

For additional information: http://www.karger.com/INT


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001;358:958–965.
  2. Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J: Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003;38:645–652.
  3. Ferenci P, Fried MW, Shiffman ML, Smith CI, Marinos G, Gonçales FL Jr, Häussinger D, Diago M, Carosi G, Dhumeaux D, Craxì A, Chaneac M, Reddy KR: Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin. Hepatology 2005;43:425–433.
  4. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K, Kumada H: Predictors of viral kinetics to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b. J Med Virol 2007;79:1686–1695.
  5. Akuta N, Suzuki F, Sezaki H, Suzuki Y, Hosaka T, Someya T, Kobayashi M, Saitoh S, Watahiki S, Sato J, Matsuda M, Kobayashi M, Arase Y, Ikeda K, Kumada H: Association of amino acid substitution pattern in core protein of hepatitis C virus genotype 1b high viral load and non-virological response to interferon-ribavirin combination therapy. Intervirology 2005;48:372–380.
  6. Lin W, Kim SS, Yeung E, Kamegaya Y, Blackard JT, Kim KA, Holtzman MJ, Chung RT: Hepatitis C virus core protein blocks interferon signaling by interaction with STAT1 SH2 domain. J Med Virol 2006;80:9226–9235.
  7. Ciccaglione AR, Stellacci E, Marcantonio C, Muto V, Equestre M, Marsili G, Rapicetta M, Battistini A: Repression of interferon regulatory 1 by hepatitis C virus core protein results in inhibition of antiviral and immunomodulatory genes. J Med Virol 2007;81:202–214.
  8. Chen X, Bhandari R, Vinkemeier U, Van Den Akker F, Darnell JE Jr, Kuriyan J: A reinterpretation of the dimerization interface of the N-terminal domains of STATs. Protein Sci 2003;12:361–365.
  9. Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW: Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 2002;285:1–24.
  10. ten Hoeve J, de Jesus Ibarra-Sanchez M, Fu Y, Zhu W, Tremblay M, David M, Shuai K: Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol Cell Biol 2002;22:5662–5668.
  11. Novick D, Cohen B, Rubinstein M: The human interferon alpha/beta receptor: characterization and molecular cloning. Cell 1994;77:391–400.
  12. Domanski P, Witte M, Kellum M, Rubinstein M, Hackett R, Pitha P, Colamonici OP: Cloning and expression of a long form of the beta subunit of the interferon alpha beta receptor that is required for signaling. J Biol Chem 1995;270:21606–20611.
  13. Mizukoshi E, Kaneko S, Yanagi M, Ohno H, Kaji K, Terasaki S, Shimoda A, Matsushita E, Kobayashi K: Expression of interferon alpha/beta receptor in the liver of chronic hepatitis C patients. J Med Virol 1998;56:217–223.
  14. Yatsuhashi H, Fujino T, Matsumoto T, Inoue O, Koga M, Yano M: Immunohistochemical analysis of hepatic interferon alpha-beta receptor level: relationship between receptor expression and response to interferon therapy in patients with chronic hepatitis C. J Hepatol 1999;30:995–1003.
  15. Mathai J, Shimoda K, Banner BF, Mori M, Bonkovsky HL, Barnard GF: IFN alpha-receptor mRNA expression in a United States sample with predominantly genotype 1a/I chronic hepatitis C liver biopsies correlates with response to IFN therapy. J Interferon Cytokine Res 1999;19:1011–1018.
  16. Morita K, Tanaka K, Saito S, Kitamura T, Kiba T, Fujii T, Numata K, Sekihara H: Expression of interferon receptor genes in the liver as a predictor of interferon response in patients with chronic hepatitis C. J Med Virol 1999;58:359–365.
  17. Yamaguchi Y, Hino K, Fujiwara D, Ren F, Katoh Y, Okita K: Expression of type I interferon receptor in liver and peripheral blood mononuclear cells in chronic hepatitis C patients. Dig Dis Sci 2002;47:1611–1617.
  18. Tochizawa S, Akamatsu S, Sugiyama Y, Muraguchi M, Ohmoto Y, Ono Y, Ishikawa H, Tanigami A, Sumida T, Mori T: A flow cytometric method for determination of the interferon receptor IFNAR-2 subsets in peripheral blood leukocyte subsets. J Pharmacol Toxicol Method 2004;50:59–66.
  19. Ren F, Hino K, Yamaguchi Y, Okazaki M, Kitase A, Satoh Y, Korenaga M, Okuda M, Okita K: Hepatitis C virus infection upregulates expression of the type I interferon receptor in human peripheral blood mononuclear cells. Hepatol Res 2003;26:15–22.
  20. Knodell RG, Ishak KG, Black WC, Chen TS, Craig R,Kaplowitz N, Kiernan TW, Wollman J: Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic hepatitis. Hepatology 1981;1:431–435.
  21. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ: Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994;19:1513–1520.