1887

Abstract

Hepatitis C virus (HCV) is a major cause of severe liver disease, and one major contributing factor is thought to involve a dysfunction of virus-specific T-cells. T-cell receptor (TCR) gene therapy with HCV-specific TCRs would increase the number of effector T-cells to promote virus clearance. We therefore took advantage of HLA-A2 transgenic mice to generate multiple TCR candidates against HCV using DNA vaccination followed by generation of stable T-cell–BW (T-BW) tumour hybrid cells. Using this approach, large numbers of non-structural protein 3 (NS3)-specific functional T-BW hybrids can be generated efficiently. These predominantly target the genetically stable HCV genotype 1 NS3 CTL epitope, frequently associated with clearance of HCV in humans. These T-BW hybrid clones recognized the NS3 peptide with a high avidity. The hybridoma effectively recognized virus variants and targeted cells with low HLA-A2 expression, which has not been reported previously. Importantly, high-avidity murine TCRs effectively redirected human non-HCV-specific T-lymphocytes to recognize human hepatoma cells with HCV RNA replication driven by a subgenomic HCV replicon. Taken together, TCR candidates with a range of functional avidities, which can be used to study immune recognition of HCV-positive targets, have been generated. This has implications for TCR-related immunotherapy against HCV.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.037903-0
2012-02-01
2019-10-18
Loading full text...

Full text loading...

/deliver/fulltext/jgv/93/2/247.html?itemId=/content/journal/jgv/10.1099/vir.0.037903-0&mimeType=html&fmt=ahah

References

  1. Accapezzato D. , Visco V. , Francavilla V. , Molette C. , Donato T. , Paroli M. , Mondelli M. U. , Doria M. , Torrisi M. R. , Barnaba V. . ( 2005; ). Chloroquine enhances human CD8+ T cell responses against soluble antigens in vivo . . J Exp Med 202:, 817–828. [CrossRef] [PubMed]
    [Google Scholar]
  2. Ahlén G. , Söderholm J. , Tjelle T. , Kjeken R. , Frelin L. , Höglund U. , Blomberg P. , Fons M. , Mathiesen I. , Sällberg M. . ( 2007; ). In vivo electroporation enhances the immunogenicity of hepatitis C virus nonstructural 3/4A DNA by increased local DNA uptake, protein expression, inflammation, and infiltration of CD3+ T cells. . J Immunol 179:, 4741–4753.[PubMed] [CrossRef]
    [Google Scholar]
  3. Ahmed R. , Akondy R. S. . ( 2011; ). Insights into human CD8+ T-cell memory using the yellow fever and smallpox vaccines. . Immunol Cell Biol 89:, 340–345. [CrossRef] [PubMed]
    [Google Scholar]
  4. Alter H. . ( 2006; ). Viral hepatitis. . Hepatology 43: (Suppl. 1 ), S230–S234. [CrossRef] [PubMed]
    [Google Scholar]
  5. Badr G. , Bédard N. , Abdel-Hakeem M. S. , Trautmann L. , Willems B. , Villeneuve J. P. , Haddad E. K. , Sékaly R. P. , Bruneau J. , Shoukry N. H. . ( 2008; ). Early interferon therapy for hepatitis C virus infection rescues polyfunctional, long-lived CD8+ memory T cells. . J Virol 82:, 10017–10031. [CrossRef] [PubMed]
    [Google Scholar]
  6. Bain C. , Fatmi A. , Zoulim F. , Zarski J. P. , Trépo C. , Inchauspé G. . ( 2001; ). Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection. . Gastroenterology 120:, 512–524. [CrossRef] [PubMed]
    [Google Scholar]
  7. Bartenschlager R. , Sparacio S. . ( 2007; ). Hepatitis C virus molecular clones and their replication capacity in vivo and in cell culture. . Virus Res 127:, 195–207. [CrossRef] [PubMed]
    [Google Scholar]
  8. Barth H. , Ulsenheimer A. , Pape G. R. , Diepolder H. M. , Hoffmann M. , Neumann-Haefelin C. , Thimme R. , Henneke P. , Klein R. . & other authors ( 2005; ). Uptake and presentation of hepatitis C virus-like particles by human dendritic cells. . Blood 105:, 3605–3614. [CrossRef] [PubMed]
    [Google Scholar]
  9. Barth H. , Schnober E. K. , Neumann-Haefelin C. , Thumann C. , Zeisel M. B. , Diepolder H. M. , Hu Z. , Liang T. J. , Blum H. E. . & other authors ( 2008; ). Scavenger receptor class B is required for hepatitis C virus uptake and cross-presentation by human dendritic cells. . J Virol 82:, 3466–3479. [CrossRef] [PubMed]
    [Google Scholar]
  10. Brinster C. , Muguet S. , Lone Y. C. , Boucreux D. , Renard N. , Fournillier A. , Lemonnier F. , Inchauspé G. . ( 2001; ). Different hepatitis C virus nonstructural protein 3 (Ns3)-DNA-expressing vaccines induce in HLA-A2.1 transgenic mice stable cytotoxic T lymphocytes that target one major epitope. . Hepatology 34:, 1206–1217. [CrossRef] [PubMed]
    [Google Scholar]
  11. Cabrera R. , Tu Z. , Xu Y. , Firpi R. J. , Rosen H. R. , Liu C. , Nelson D. R. . ( 2004; ). An immunomodulatory role for CD4+CD25+ regulatory T lymphocytes in hepatitis C virus infection. . Hepatology 40:, 1062–1071. [CrossRef] [PubMed]
    [Google Scholar]
  12. Ciuffreda D. , Comte D. , Cavassini M. , Giostra E. , Bühler L. , Perruchoud M. , Heim M. H. , Battegay M. , Genné D. . & other authors ( 2008; ). Polyfunctional HCV-specific T-cell responses are associated with effective control of HCV replication. . Eur J Immunol 38:, 2665–2677. [CrossRef] [PubMed]
    [Google Scholar]
  13. Cox A. L. , Mosbruger T. , Lauer G. M. , Pardoll D. , Thomas D. L. , Ray S. C. . ( 2005; ). Comprehensive analyses of CD8+ T cell responses during longitudinal study of acute human hepatitis C. . Hepatology 42:, 104–112. [CrossRef] [PubMed]
    [Google Scholar]
  14. Cucchiarini M. , Kammer A. R. , Grabscheid B. , Diepolder H. M. , Gerlach T. J. , Grüner N. , Santantonio T. , Reichen J. , Pape G. R. , Cerny A. . ( 2000; ). Vigorous peripheral blood cytotoxic T cell response during the acute phase of hepatitis C virus infection. . Cell Immunol 203:, 111–123. [CrossRef] [PubMed]
    [Google Scholar]
  15. Davis J. L. , Theoret M. R. , Zheng Z. , Lamers C. H. , Rosenberg S. A. , Morgan R. A. . ( 2010; ). Development of human anti-murine T-cell receptor antibodies in both responding and nonresponding patients enrolled in TCR gene therapy trials. . Clin Cancer Res 16:, 5852–5861. [CrossRef] [PubMed]
    [Google Scholar]
  16. Diepolder H. M. , Zachoval R. , Hoffmann R. M. , Jung M. C. , Gerlach T. , Pape G. R. . ( 1996; ). The role of hepatitis C virus specific CD4+ T lymphocytes in acute and chronic hepatitis C. . J Mol Med (Berl) 74:, 583–588.[PubMed] [CrossRef]
    [Google Scholar]
  17. Frelin L. , Alheim M. , Chen A. , Söderholm J. , Rozell B. , Barnfield C. , Liljeström P. , Sällberg M. . ( 2003; ). Low dose and gene gun immunization with a hepatitis C virus nonstructural (NS) 3 DNA-based vaccine containing NS4A inhibit NS3/4A-expressing tumors in vivo . . Gene Ther 10:, 686–699. [CrossRef] [PubMed]
    [Google Scholar]
  18. Frelin L. , Ahlén G. , Alheim M. , Weiland O. , Barnfield C. , Liljeström P. , Sällberg M. . ( 2004; ). Codon optimization and mRNA amplification effectively enhances the immunogenicity of the hepatitis C virus nonstructural 3/4A gene. . Gene Ther 11:, 522–533. [CrossRef] [PubMed]
    [Google Scholar]
  19. Fytili P. , Dalekos G. N. , Schlaphoff V. , Suneetha P. V. , Sarrazin C. , Zauner W. , Zachou K. , Berg T. , Manns M. P. . & other authors ( 2008; ). Cross-genotype-reactivity of the immunodominant HCV CD8 T-cell epitope NS3-1073. . Vaccine 26:, 3818–3826. [CrossRef] [PubMed]
    [Google Scholar]
  20. Goutagny N. , Fatmi A. , De Ledinghen V. , Penin F. , Couzigou P. , Inchauspé G. , Bain C. . ( 2003; ). Evidence of viral replication in circulating dendritic cells during hepatitis C virus infection. . J Infect Dis 187:, 1951–1958. [CrossRef] [PubMed]
    [Google Scholar]
  21. Himoudi N. , Abraham J. D. , Fournillier A. , Lone Y. C. , Joubert A. , Op De Beeck A. , Freida D. , Lemonnier F. , Kieny M. P. , Inchauspé G. . ( 2002; ). Comparative vaccine studies in HLA-A2.1-transgenic mice reveal a clustered organization of epitopes presented in hepatitis C virus natural infection. . J Virol 76:, 12735–12746. [CrossRef] [PubMed]
    [Google Scholar]
  22. Jäger E. , Höhn H. , Karbach J. , Momburg F. , Castelli C. , Knuth A. , Seliger B. , Maeurer M. J. . ( 1999; ). Cytotoxic T lymphocytes define multiple peptide isoforms derived from the melanoma-associated antigen MART-1/Melan-A. . Int J Cancer 81:, 979–984. [CrossRef] [PubMed]
    [Google Scholar]
  23. Kantzanou M. , Lucas M. , Barnes E. , Komatsu H. , Dusheiko G. , Ward S. , Harcourt G. , Klenerman P. . ( 2003; ). Viral escape and T cell exhaustion in hepatitis C virus infection analysed using Class I peptide tetramers. . Immunol Lett 85:, 165–171. [CrossRef] [PubMed]
    [Google Scholar]
  24. Kasprowicz V. , Ward S. M. , Turner A. , Grammatikos A. , Nolan B. E. , Lewis-Ximenez L. , Sharp C. , Woodruff J. , Fleming V. M. . & other authors ( 2008; ). Defining the directionality and quality of influenza virus-specific CD8+ T cell cross-reactivity in individuals infected with hepatitis C virus. . J Clin Invest 118:, 1143–1153.[PubMed]
    [Google Scholar]
  25. Kieback E. , Uckert W. . ( 2010; ). Enhanced T cell receptor gene therapy for cancer. . Expert Opin Biol Ther 10:, 749–762. [CrossRef] [PubMed]
    [Google Scholar]
  26. Lapenta C. , Santini S. M. , Spada M. , Donati S. , Urbani F. , Accapezzato D. , Franceschini D. , Andreotti M. , Barnaba V. , Belardelli F. . ( 2006; ). IFN-α-conditioned dendritic cells are highly efficient in inducing cross-priming CD8+ T cells against exogenous viral antigens. . Eur J Immunol 36:, 2046–2060. [CrossRef] [PubMed]
    [Google Scholar]
  27. Lechner F. , Gruener N. H. , Urbani S. , Uggeri J. , Santantonio T. , Kammer A. R. , Cerny A. , Phillips R. , Ferrari C. . & other authors ( 2000; ). CD8+ T lymphocyte responses are induced during acute hepatitis C virus infection but are not sustained. . Eur J Immunol 30:, 2479–2487. [CrossRef] [PubMed]
    [Google Scholar]
  28. McKee M. D. , Roszkowski J. J. , Nishimura M. I. . ( 2005; ). T cell avidity and tumor recognition: implications and therapeutic strategies. . J Transl Med 3:, 35. [CrossRef] [PubMed]
    [Google Scholar]
  29. Miles J. J. , Thammanichanond D. , Moneer S. , Nivarthi U. K. , Kjer-Nielsen L. , Tracy S. L. , Aitken C. K. , Brennan R. M. , Zeng W. . & other authors ( 2011; ). Antigen-driven patterns of TCR bias are shared across diverse outcomes of human hepatitis C virus infection. . J Immunol 186:, 901–912. [CrossRef] [PubMed]
    [Google Scholar]
  30. Nattermann J. , Zimmermann H. , Iwan A. , von Lilienfeld-Toal M. , Leifeld L. , Nischalke H. D. , Langhans B. , Sauerbruch T. , Spengler U. . ( 2006; ). Hepatitis C virus E2 and CD81 interaction may be associated with altered trafficking of dendritic cells in chronic hepatitis C. . Hepatology 44:, 945–954. [CrossRef] [PubMed]
    [Google Scholar]
  31. Neveu B. , Debeaupuis E. , Echasserieau K. , le Moullac-Vaidye B. , Gassin M. , Jegou L. , Decalf J. , Albert M. , Ferry N. . & other authors ( 2008; ). Selection of high-avidity CD8 T cells correlates with control of hepatitis C virus infection. . Hepatology 48:, 713–722. [CrossRef] [PubMed]
    [Google Scholar]
  32. Pape G. R. , Gerlach T. J. , Diepolder H. M. , Grüner N. , Jung M. , Santantonio T. . ( 1999; ). Role of the specific T-cell response for clearance and control of hepatitis C virus. . J Viral Hepat 6: (Suppl. 1), 36–40. [CrossRef] [PubMed]
    [Google Scholar]
  33. Pascolo S. , Bervas N. , Ure J. M. , Smith A. G. , Lemonnier F. A. , Pérarnau B. . ( 1997; ). HLA-A2.1-restricted education and cytolytic activity of CD8+ T lymphocytes from β2 microglobulin (β2m) HLA-A2.1 monochain transgenic H-2Db β2m double knockout mice. . J Exp Med 185:, 2043–2051. [CrossRef] [PubMed]
    [Google Scholar]
  34. Radziewicz H. , Ibegbu C. C. , Fernandez M. L. , Workowski K. A. , Obideen K. , Wehbi M. , Hanson H. L. , Steinberg J. P. , Masopust D. . & other authors ( 2007; ). Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. . J Virol 81:, 2545–2553. [CrossRef] [PubMed]
    [Google Scholar]
  35. Rantala M. , van de Laar M. J. . ( 2008; ). Surveillance and epidemiology of hepatitis B and C in Europe – a review. . Euro Surveill 13:, pii: 18880.[PubMed]
    [Google Scholar]
  36. Rock K. L. , Rothstein L. , Gamble S. . ( 1990; ). Generation of class I MHC-restricted T-T hybridomas. . J Immunol 145:, 804–811.[PubMed]
    [Google Scholar]
  37. Roszkowski J. J. , Yu D. C. , Rubinstein M. P. , McKee M. D. , Cole D. J. , Nishimura M. I. . ( 2003; ). CD8-independent tumor cell recognition is a property of the T cell receptor and not the T cell. . J Immunol 170:, 2582–2589.[PubMed] [CrossRef]
    [Google Scholar]
  38. Schulze zur Wiesch J. , Lauer G. M. , Day C. L. , Kim A. Y. , Ouchi K. , Duncan J. E. , Wurcel A. G. , Timm J. , Jones A. M. . & other authors ( 2005; ). Broad repertoire of the CD4+ Th cell response in spontaneously controlled hepatitis C virus infection includes dominant and highly promiscuous epitopes. . J Immunol 175:, 3603–3613.[PubMed] [CrossRef]
    [Google Scholar]
  39. Söderholm J. , Ahlén G. , Kaul A. , Frelin L. , Alheim M. , Barnfield C. , Liljeström P. , Weiland O. , Milich D. R. . & other authors ( 2006; ). Relation between viral fitness and immune escape within the hepatitis C virus protease. . Gut 55:, 266–274. [CrossRef] [PubMed]
    [Google Scholar]
  40. Sugimoto K. , Ikeda F. , Stadanlick J. , Nunes F. A. , Alter H. J. , Chang K. M. . ( 2003; ). Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection. . Hepatology 38:, 1437–1448.[PubMed]
    [Google Scholar]
  41. Thompson A. J. , McHutchison J. G. . ( 2009; ). Review article: investigational agents for chronic hepatitis C. . Aliment Pharmacol Ther 29:, 689–705. [CrossRef] [PubMed]
    [Google Scholar]
  42. Turner S. J. , Doherty P. C. , McCluskey J. , Rossjohn J. . ( 2006; ). Structural determinants of T-cell receptor bias in immunity. . Nat Rev Immunol 6:, 883–894. [CrossRef] [PubMed]
    [Google Scholar]
  43. Ulsenheimer A. , Gerlach J. T. , Jung M. C. , Gruener N. , Wächtler M. , Backmund M. , Santantonio T. , Schraut W. , Heeg M. H. . & other authors ( 2005; ). Plasmacytoid dendritic cells in acute and chronic hepatitis C virus infection. . Hepatology 41:, 643–651. [CrossRef] [PubMed]
    [Google Scholar]
  44. Urbani S. , Amadei B. , Fisicaro P. , Pilli M. , Missale G. , Bertoletti A. , Ferrari C. . ( 2005; ). Heterologous T cell immunity in severe hepatitis C virus infection. . J Exp Med 201:, 675–680. [CrossRef] [PubMed]
    [Google Scholar]
  45. Wedemeyer H. , Mizukoshi E. , Davis A. R. , Bennink J. R. , Rehermann B. . ( 2001; ). Cross-reactivity between hepatitis C virus and influenza A virus determinant-specific cytotoxic T cells. . J Virol 75:, 11392–11400. [CrossRef] [PubMed]
    [Google Scholar]
  46. Wedemeyer H. , He X. S. , Nascimbeni M. , Davis A. R. , Greenberg H. B. , Hoofnagle J. H. , Liang T. J. , Alter H. , Rehermann B. . ( 2002; ). Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection. . J Immunol 169:, 3447–3458.[PubMed] [CrossRef]
    [Google Scholar]
  47. Wertheimer A. M. , Miner C. , Lewinsohn D. M. , Sasaki A. W. , Kaufman E. , Rosen H. R. . ( 2003; ). Novel CD4+ and CD8+ T-cell determinants within the NS3 protein in subjects with spontaneously resolved HCV infection. . Hepatology 37:, 577–589. [CrossRef] [PubMed]
    [Google Scholar]
  48. Wertheimer A. M. , Polyak S. J. , Leistikow R. , Rosen H. R. . ( 2007; ). Engulfment of apoptotic cells expressing HCV proteins leads to differential chemokine expression and STAT signaling in human dendritic cells. . Hepatology 45:, 1422–1432. [CrossRef] [PubMed]
    [Google Scholar]
  49. Zhang Y. , Liu Y. , Moxley K. M. , Golden-Mason L. , Hughes M. G. , Liu T. , Heemskerk M. H. , Rosen H. R. , Nishimura M. I. . ( 2010; ). Transduction of human T cells with a novel T-cell receptor confers anti-HCV reactivity. . PLoS Pathog 6:, e1001018. [CrossRef] [PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.037903-0
Loading
/content/journal/jgv/10.1099/vir.0.037903-0
Loading

Data & Media loading...

Supplements

Supplementary figure 

PDF

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error