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Vol. 48, No. 6, 2005
Issue release date: November–December 2005
Intervirology 2005;48:372–380
(DOI:10.1159/000086064)

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

Akuta N.a · Suzuki F.a · Sezaki H.a · Suzuki Y.a · Hosaka T.a · Someya T.a · Kobayashi M.a · Saitoh S.a · Watahiki S.b · Sato J.b · Matsuda M.b · Kobayashi M.b · Arase Y.a · Ikeda K.a · Kumada H.a
aDepartment of Gastroenterology and bLiver Research Laboratory, Toranomon Hospital, Tokyo, Japan
email Corresponding Author

Abstract

Objective: Patients with high titer (≧100 kIU/ml) of hepatitis C virus (HCV) genotype 1b do not achieve highly sustained virological response rates to combination therapy with interferon plus ribavirin. Non-virological responders (NVRs, namely ultimate resistant cases) who do not achieve HCV-RNA negativity during treatment are also encountered. We investigated the pretreatment virological features of NVRs. Methods: We evaluated 50 consecutive Japanese adults with high titer of HCV genotype 1b who received combination therapy for 48 weeks. We investigated the pretreatment substitution patterns in amino acids 1–191 of the core region and amino acids 2209–2248 of NS5A, and early viral kinetics. Results: Overall, a non-virological response was noted in 12 (24%) patients. Multivariate analysis identified serum albumin <3.9 g/dl, substitutions of amino acid 70 in the core region, and substitutions of amino acid 91 as independent and significant factors associated with a non-virological response. Especially, substitutions of arginine (R) by glutamine (Q) at amino acid 70, and/or leucine (L) by methionine (M) at amino acid 91 were significantly more common in NVRs. The falls in HCV-RNA levels during treatment in patients with specific substitutions in the core region were significantly less than in those without such substitutions. Conclusions: Our results suggest that serum albumin and amino acid substitution patterns in the core region in patients with high titers of HCV genotype 1b may have an effect on combination therapy in NVRs. Further large-scale studies are required to examine the role of amino acid substitutions specific to a non-virological response to combination therapy.


 goto top of outline Key Words

  • Hepatitis C virus
  • Genotype 1b
  • Albumin
  • Core region
  • Interferon sensitivity-determining region
  • Interferon
  • Ribavirin
  • Non-virological responder
  • Viral kinetics

 goto top of outline Abstract

Objective: Patients with high titer (≥100 kIU/ml) of hepatitis C virus (HCV) genotype 1b do not achieve highly sustained virological response rates to combination therapy with interferon plus ribavirin. Non-virological responders (NVRs, namely ultimate resistant cases) who do not achieve HCV-RNA negativity during treatment are also encountered. We investigated the pretreatment virological features of NVRs. Methods: We evaluated 50 consecutive Japanese adults with high titer of HCV genotype 1b who received combination therapy for 48 weeks. We investigated the pretreatment substitution patterns in amino acids 1–191 of the core region and amino acids 2209–2248 of NS5A, and early viral kinetics. Results: Overall, a non-virological response was noted in 12 (24%) patients. Multivariate analysis identified serum albumin <3.9 g/dl, substitutions of amino acid 70 in the core region, and substitutions of amino acid 91 as independent and significant factors associated with a non-virological response. Especially, substitutions of arginine (R) by glutamine (Q) at amino acid 70, and/or leucine (L) by methionine (M) at amino acid 91 were significantly more common in NVRs. The falls in HCV-RNA levels during treatment in patients with specific substitutions in the core region were significantly less than in those without such substitutions. Conclusions: Our results suggest that serum albumin and amino acid substitution patterns in the core region in patients with high titers of HCV genotype 1b may have an effect on combination therapy in NVRs. Further large-scale studies are required to examine the role of amino acid substitutions specific to a non-virological response to combination therapy.

Copyright © 2005 S. Karger AG, Basel


 goto top of outline References
  1. Niederau C, Lange S, Heintges T, Erhardt A, Buschkamp M, Hurter D, Nawrocki M, Kruska L, Hensel F, Petry W, Haussinger D: Prognosis of chronic hepatitis C: Results of a large, prospective cohort study. Hepatology 1998;28:1687–1695.
  2. Ikeda K, Saitoh S, Suzuki Y, Kobayashi M, Tsubota A, Koida I, Arase Y, Fukuda M, Chayama K, Murashima N, Kumada H: Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: A prospective observation of 2215 patients. J Hepatol 1998;28:930–938.
  3. Kenny-Walsh E: Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. N Engl J Med 1999;340:1228–1233.
  4. Akuta N, Chayama K, Suzuki F, Someya T, Kobayashi M, Tsubota A, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Kumada H: Risk factors of hepatitis C virus-related liver cirrhosis in young adults: Positive family history of liver disease and transporter associated with antigen processing 2 (TAP2) *0201 allele. J Med Virol 2001;64:109–116.
  5. Ikeda K, Saitoh S, Arase Y, Chayama K, Suzuki Y, Kobayashi M, Tsubota A, Nakamura I, Murashima N, Kumada H, Kawanishi M: Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: A long-term observation study of 1643 patients using statistical bias correction with proportional hazard analysis. Hepatology 1999;29:1124–1130.
  6. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling MH, 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.
  7. Fried MW, Shiffman ML, Reddy R, Smith C, Marinos G, Gonçales FL, Häussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–982.
  8. Kanai K, Kako M, Okamoto H: HCV genotypes in chronic hepatitis C and response to interferon. Lancet 1992;339:1543.
  9. Hino K, Sainokami S, Shimoda K, Iino S, Wang Y, Okamoto H, Miyakawa Y, Mayumi M: Genotypes and titers of hepatitis C virus for predicting response to interferon in patients with chronic hepatitis C. J Med Virol 1994;42:299–305.
  10. Mahaney K, Tedeschi V, Maertens G, Di Bisceglie AM, Vergalla J, Hoofnagle JH, Sallie R: Genotypic analysis of hepatitis C virus in American patients. Hepatology 1994;20:1405–1411.
  11. Tsubota A, Chayama K, Ikeda K, Arase Y, Koida I, Saitoh S, Hashimoto M, Iwasaki S, Kobayashi M, Kumada H: Factors predictive of response to interferon-α therapy in hepatitis C virus infection. Hepatology 1994;19:1088–1094.
  12. Akuta N, Suzuki F, Tsubota A, Suzuki Y, Someya T, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kumada H: Efficacy of interferon monotherapy to 394 consecutive naive cases infected with hepatitis C virus genotype 2a in Japan: Therapy efficacy as consequence of tripartite interaction of viral, host and interferon treatment-related factors. J Hepatol 2002;37:831–836.
  13. Lalvakolanu DV: Alternate interferon signaling pathways. Pharmacol Ther 2003;100:1–29.
  14. Blindenbacher A, Duong FH, Hunziker L, Stutvoet ST, Wang X, Terracciano L, Moradpour D, Blum HE, Alonzi T, Tripodi M, La Monica N, Heim MH: Expression of hepatitis C virus proteins inhibits interferon α signaling in the liver of transgenic mice. Gastroenterology 2003;124:1465–1475.
  15. Bode JG, Ludwig S, Ehrhardt C, Albrecht U, Erhardt A, Schaper F, Heinrich PC, Häussinger D: IFN-α antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling-3. FASEB J 2003;17:488–490.
  16. Melén K, Fagerlund R, Nyqvist M, Keskinen P, Julkunen I: Expression of hepatitis C virus core protein inhibits interferon-induced nuclear import of STATs. J Med Virol 2004;73:536–547.
  17. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Izumi N, Marumo F, Sato C: Comparison of full-length sequences of interferon sensitive and resistant hepatitis C virus 1b. J Clin Invest 1995;96:224–230.
  18. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Ogura Y, Izumi N, Marumo F, Sato C: Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N Engl J Med 1996;334:77–81.
  19. Chayama K, Tsubota A, Arase Y, Saitoh S, Koida I, Ikeda K, Matsumoto T, Kobayashi M, Iwasaki S, Koyama S, Morinaga T, Kumada H: Genotypic subtyping of hepatitis C virus. J Gastroenterol Hepatol 1993;8:150–156.
  20. Desmet VJ, Gerber M, Hoofnagle JH, Manna M, Scheuer PJ: Classification of chronic hepatitis: Diagnosis, grading and staging. Hepatology 1994;19:1513–1520.
  21. D’Alessandro AM, Kalayouglu M, Sollinger HW, Hoffmann RM, Reed A, Knechtle SJ, Pirsch JD, Hafez GR, Lorentzen D, Belzer FO: The predictive value of donor liver biopsies for the development of primary nonfunction after orthotopic liver transplantation. Transplantation 1991;51:157–163.
  22. Kato N, Hijikata M, Ootsuyama Y, Nakagawa M, Ohkoshi S, Sugimura T, Shimotohno K: Molecular cloning of the human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis. Proc Natl Acad Sci USA 1990;87:9524–9528.
  23. Kwok S, Higuchi R: Avoiding false positives with PCR. Nature 1989;339:237–238.
  24. Sherlock SH, Dooley JA: Disease of the Liver and Biliary System, ed 9. London, Blackwell Scientific, 1992.
  25. Jouet P, Roudot-Thoraval F, Dhumeaux D, Metreau JM: Comparative efficacy of interferon alfa in cirrhotic and noncirrhotic patients with non-A, non-B, C hepatitis. Le Groupe Français pour l’Etude du Traitement des Hépatites Chroniques NANB/C. Gastroenterology 1994;106:686–690.
  26. Poynard T, McHutchinson J, Goodman Z, Ling MH, Albrecht J: Is an ‘a la carte’ combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C? The ALGOVIRC Group. Hepatology 2000;31:211–218.
  27. Bruno S, Camma C, Di Marco V, Rumi M, Vinci M, Camozzi M, Rebucci C, Di Bona D, Colombo M, Craxi A, Mondelli MU, Pinzello G: Peginterferon alfa-2b plus ribavirin for naïve patients with genotype 1 chronic hepatitis C: A randomized controlled trial. J Hepatol 2004;41:474–481.
  28. Chang KC, Hansen E, Foroni L, Lida J, Goldspink G: Molecular and functional analysis of the virus- and interferon-inducible human MxA promoter. Arch Virol 1991;117:1–15.
  29. Ronni T, Matikainen S, Lehtonen A, Palvimo J, Dellis J, Van Eylen F, Goetschy JF, Horisberger M, Content J, Julkunen I: The proximal interferon-stimulated response elements are essential for interferon responsiveness: A promoter analysis of the antiviral MxA gene. J Interferon Cytokine Res 1998;18:773–781.
  30. Benech P, Vigneron M, Peretz D, Revel M, Chebath J: Interferon-responsive regulatory elements in the promoter of the human 2′,5′-oligo(A) synthetase gene. Mol Cell Biol 1987;7:4498–4504.
  31. Wang Q, Floyd-Smith G: The p69/71 2–5A synthetase promoter contains multiple regulatory elements required for interferon-alpha-induced expression. DNA Cell Biol 1997;16:1385–1394.
  32. Auernhammer CJ, Melmed S: The central role of SOCS-3 in integrating the neuro-immunoendocrine interface. J Clin Invest 2001;108:1735–1740.
  33. Fujimoto M, Naka T: Regulation of cytokine signaling by SOCS family molecules. Trends Immunol 2003;24:659–666.
  34. Song MM, Shuai K: The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities. J Biol Chem 1998;273:35056–35062.
  35. Stoiber D, Kovarik P, Cohney S, Johnston JA, Steinlein P, Decker T: Lipopolysaccharide induces in macrophages the synthesis of the suppressor of cytokine signaling 3 and suppresses signal transduction in response to the activating factor IFN-gamma. J Immunol 1999;163:2640–2647.
  36. Alexander WS: Suppressors of cytokine signaling (SOCS) in the immune system. Nat Rev Immunol 2002;2:410–416.
  37. Vlotides G, Sörensen AS, Kopp F, Zitzmann K, Cengic N, Brand S, Zachoval R, Auernhammer CJ: SOCS-1 and SCOS-3 inhibit IFN-α-induced expression of the antiviral 2,5-OAS and MxA. Biochem Biophys Res Commun 2004;320:1007–1014.
  38. Akuta N, Suzuki F, Tsubota A, Suzuki Y, Hosaka T, Someya T, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kumada H: Association of amino acid substitution pattern in nonstructural protein 5A of hepatitis C virus genotype2a low viral load and response to interferon monotherapy. J Med Virol 2003;69:376–383.
  39. Gale MJ, Korth MJ, Tang NM, Tan SL, Hopkins DA, Dever TE, Polyak SJ, Gretch DR, Katze MG: Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology 1997;230:217–227.
  40. Chieux V, Hober D, Harvey J, Lion G, Lucidarme D, Forzy G, Duhamel M, Cousin J, Ducoulombier H, Wattre P: The MxA protein levels in whole blood lysates of patients with various viral infections. J Virol Methods 1998;70:183–191.
  41. Fernandez M, Quiroga JA, Martin J, Ierrero M, Pardo M, Horisberger MA, Carreno V: In vivo and in vitro induction of MxA protein in peripheral blood mononuclear cells from patients chronically infected with hepatitis C virus. J Infect Dis 1999;180:262–267.
  42. Antonelli G, Simeoni E, Turriziani O, Tesoro R, Redaelli A, Roffi L, Antonelli L, Pistello M, Dianzai F: Correlation of interferon-induced expression of MxA mRNA in peripheral blood mononuclear cells with the response of patients with chronic hepatitis C to IFN-α therapy. J Interferon Cytokine Res 1999;19:243–251.

 goto top of outline Author Contacts

Norio Akuta, MD
Department of Gastroenterology, Toranomon Hospital
2-2-2 Toranomon, Minato-ku
Tokyo 105-0001 (Japan)
Tel. +81 44 877 5111, Fax +81 44 860 1623, E-Mail akuta-gi@umin.ac.jp


 goto top of outline Article Information

Received: November 10, 2004
Accepted after revision: December 9, 2004
Number of Print Pages : 9
Number of Figures : 1, Number of Tables : 4, Number of References : 42


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 48, No. 6, Year 2005 (Cover Date: November-December 2005)

Journal Editor: Liebert, U.G. (Leipzig)
ISSN: 0300–5526 (print), 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

Objective: Patients with high titer (≧100 kIU/ml) of hepatitis C virus (HCV) genotype 1b do not achieve highly sustained virological response rates to combination therapy with interferon plus ribavirin. Non-virological responders (NVRs, namely ultimate resistant cases) who do not achieve HCV-RNA negativity during treatment are also encountered. We investigated the pretreatment virological features of NVRs. Methods: We evaluated 50 consecutive Japanese adults with high titer of HCV genotype 1b who received combination therapy for 48 weeks. We investigated the pretreatment substitution patterns in amino acids 1–191 of the core region and amino acids 2209–2248 of NS5A, and early viral kinetics. Results: Overall, a non-virological response was noted in 12 (24%) patients. Multivariate analysis identified serum albumin <3.9 g/dl, substitutions of amino acid 70 in the core region, and substitutions of amino acid 91 as independent and significant factors associated with a non-virological response. Especially, substitutions of arginine (R) by glutamine (Q) at amino acid 70, and/or leucine (L) by methionine (M) at amino acid 91 were significantly more common in NVRs. The falls in HCV-RNA levels during treatment in patients with specific substitutions in the core region were significantly less than in those without such substitutions. Conclusions: Our results suggest that serum albumin and amino acid substitution patterns in the core region in patients with high titers of HCV genotype 1b may have an effect on combination therapy in NVRs. Further large-scale studies are required to examine the role of amino acid substitutions specific to a non-virological response to combination therapy.



 goto top of outline Author Contacts

Norio Akuta, MD
Department of Gastroenterology, Toranomon Hospital
2-2-2 Toranomon, Minato-ku
Tokyo 105-0001 (Japan)
Tel. +81 44 877 5111, Fax +81 44 860 1623, E-Mail akuta-gi@umin.ac.jp


 goto top of outline Article Information

Received: November 10, 2004
Accepted after revision: December 9, 2004
Number of Print Pages : 9
Number of Figures : 1, Number of Tables : 4, Number of References : 42


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 48, No. 6, Year 2005 (Cover Date: November-December 2005)

Journal Editor: Liebert, U.G. (Leipzig)
ISSN: 0300–5526 (print), 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. Niederau C, Lange S, Heintges T, Erhardt A, Buschkamp M, Hurter D, Nawrocki M, Kruska L, Hensel F, Petry W, Haussinger D: Prognosis of chronic hepatitis C: Results of a large, prospective cohort study. Hepatology 1998;28:1687–1695.
  2. Ikeda K, Saitoh S, Suzuki Y, Kobayashi M, Tsubota A, Koida I, Arase Y, Fukuda M, Chayama K, Murashima N, Kumada H: Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: A prospective observation of 2215 patients. J Hepatol 1998;28:930–938.
  3. Kenny-Walsh E: Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. N Engl J Med 1999;340:1228–1233.
  4. Akuta N, Chayama K, Suzuki F, Someya T, Kobayashi M, Tsubota A, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Kumada H: Risk factors of hepatitis C virus-related liver cirrhosis in young adults: Positive family history of liver disease and transporter associated with antigen processing 2 (TAP2) *0201 allele. J Med Virol 2001;64:109–116.
  5. Ikeda K, Saitoh S, Arase Y, Chayama K, Suzuki Y, Kobayashi M, Tsubota A, Nakamura I, Murashima N, Kumada H, Kawanishi M: Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: A long-term observation study of 1643 patients using statistical bias correction with proportional hazard analysis. Hepatology 1999;29:1124–1130.
  6. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling MH, 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.
  7. Fried MW, Shiffman ML, Reddy R, Smith C, Marinos G, Gonçales FL, Häussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–982.
  8. Kanai K, Kako M, Okamoto H: HCV genotypes in chronic hepatitis C and response to interferon. Lancet 1992;339:1543.
  9. Hino K, Sainokami S, Shimoda K, Iino S, Wang Y, Okamoto H, Miyakawa Y, Mayumi M: Genotypes and titers of hepatitis C virus for predicting response to interferon in patients with chronic hepatitis C. J Med Virol 1994;42:299–305.
  10. Mahaney K, Tedeschi V, Maertens G, Di Bisceglie AM, Vergalla J, Hoofnagle JH, Sallie R: Genotypic analysis of hepatitis C virus in American patients. Hepatology 1994;20:1405–1411.
  11. Tsubota A, Chayama K, Ikeda K, Arase Y, Koida I, Saitoh S, Hashimoto M, Iwasaki S, Kobayashi M, Kumada H: Factors predictive of response to interferon-α therapy in hepatitis C virus infection. Hepatology 1994;19:1088–1094.
  12. Akuta N, Suzuki F, Tsubota A, Suzuki Y, Someya T, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kumada H: Efficacy of interferon monotherapy to 394 consecutive naive cases infected with hepatitis C virus genotype 2a in Japan: Therapy efficacy as consequence of tripartite interaction of viral, host and interferon treatment-related factors. J Hepatol 2002;37:831–836.
  13. Lalvakolanu DV: Alternate interferon signaling pathways. Pharmacol Ther 2003;100:1–29.
  14. Blindenbacher A, Duong FH, Hunziker L, Stutvoet ST, Wang X, Terracciano L, Moradpour D, Blum HE, Alonzi T, Tripodi M, La Monica N, Heim MH: Expression of hepatitis C virus proteins inhibits interferon α signaling in the liver of transgenic mice. Gastroenterology 2003;124:1465–1475.
  15. Bode JG, Ludwig S, Ehrhardt C, Albrecht U, Erhardt A, Schaper F, Heinrich PC, Häussinger D: IFN-α antagonistic activity of HCV core protein involves induction of suppressor of cytokine signaling-3. FASEB J 2003;17:488–490.
  16. Melén K, Fagerlund R, Nyqvist M, Keskinen P, Julkunen I: Expression of hepatitis C virus core protein inhibits interferon-induced nuclear import of STATs. J Med Virol 2004;73:536–547.
  17. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Izumi N, Marumo F, Sato C: Comparison of full-length sequences of interferon sensitive and resistant hepatitis C virus 1b. J Clin Invest 1995;96:224–230.
  18. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Ogura Y, Izumi N, Marumo F, Sato C: Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N Engl J Med 1996;334:77–81.
  19. Chayama K, Tsubota A, Arase Y, Saitoh S, Koida I, Ikeda K, Matsumoto T, Kobayashi M, Iwasaki S, Koyama S, Morinaga T, Kumada H: Genotypic subtyping of hepatitis C virus. J Gastroenterol Hepatol 1993;8:150–156.
  20. Desmet VJ, Gerber M, Hoofnagle JH, Manna M, Scheuer PJ: Classification of chronic hepatitis: Diagnosis, grading and staging. Hepatology 1994;19:1513–1520.
  21. D’Alessandro AM, Kalayouglu M, Sollinger HW, Hoffmann RM, Reed A, Knechtle SJ, Pirsch JD, Hafez GR, Lorentzen D, Belzer FO: The predictive value of donor liver biopsies for the development of primary nonfunction after orthotopic liver transplantation. Transplantation 1991;51:157–163.
  22. Kato N, Hijikata M, Ootsuyama Y, Nakagawa M, Ohkoshi S, Sugimura T, Shimotohno K: Molecular cloning of the human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis. Proc Natl Acad Sci USA 1990;87:9524–9528.
  23. Kwok S, Higuchi R: Avoiding false positives with PCR. Nature 1989;339:237–238.
  24. Sherlock SH, Dooley JA: Disease of the Liver and Biliary System, ed 9. London, Blackwell Scientific, 1992.
  25. Jouet P, Roudot-Thoraval F, Dhumeaux D, Metreau JM: Comparative efficacy of interferon alfa in cirrhotic and noncirrhotic patients with non-A, non-B, C hepatitis. Le Groupe Français pour l’Etude du Traitement des Hépatites Chroniques NANB/C. Gastroenterology 1994;106:686–690.
  26. Poynard T, McHutchinson J, Goodman Z, Ling MH, Albrecht J: Is an ‘a la carte’ combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C? The ALGOVIRC Group. Hepatology 2000;31:211–218.
  27. Bruno S, Camma C, Di Marco V, Rumi M, Vinci M, Camozzi M, Rebucci C, Di Bona D, Colombo M, Craxi A, Mondelli MU, Pinzello G: Peginterferon alfa-2b plus ribavirin for naïve patients with genotype 1 chronic hepatitis C: A randomized controlled trial. J Hepatol 2004;41:474–481.
  28. Chang KC, Hansen E, Foroni L, Lida J, Goldspink G: Molecular and functional analysis of the virus- and interferon-inducible human MxA promoter. Arch Virol 1991;117:1–15.
  29. Ronni T, Matikainen S, Lehtonen A, Palvimo J, Dellis J, Van Eylen F, Goetschy JF, Horisberger M, Content J, Julkunen I: The proximal interferon-stimulated response elements are essential for interferon responsiveness: A promoter analysis of the antiviral MxA gene. J Interferon Cytokine Res 1998;18:773–781.
  30. Benech P, Vigneron M, Peretz D, Revel M, Chebath J: Interferon-responsive regulatory elements in the promoter of the human 2′,5′-oligo(A) synthetase gene. Mol Cell Biol 1987;7:4498–4504.
  31. Wang Q, Floyd-Smith G: The p69/71 2–5A synthetase promoter contains multiple regulatory elements required for interferon-alpha-induced expression. DNA Cell Biol 1997;16:1385–1394.
  32. Auernhammer CJ, Melmed S: The central role of SOCS-3 in integrating the neuro-immunoendocrine interface. J Clin Invest 2001;108:1735–1740.
  33. Fujimoto M, Naka T: Regulation of cytokine signaling by SOCS family molecules. Trends Immunol 2003;24:659–666.
  34. Song MM, Shuai K: The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities. J Biol Chem 1998;273:35056–35062.
  35. Stoiber D, Kovarik P, Cohney S, Johnston JA, Steinlein P, Decker T: Lipopolysaccharide induces in macrophages the synthesis of the suppressor of cytokine signaling 3 and suppresses signal transduction in response to the activating factor IFN-gamma. J Immunol 1999;163:2640–2647.
  36. Alexander WS: Suppressors of cytokine signaling (SOCS) in the immune system. Nat Rev Immunol 2002;2:410–416.
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