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
2020-07-12
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 Med202:817–828 [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 Immunol179:4741–4753[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 Biol89:340–345 [CrossRef][PubMed]
    [Google Scholar]
  4. Alter H.. 2006; Viral hepatitis. Hepatology43:Suppl. 1S230–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 Virol82:10017–10031 [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. Gastroenterology120:512–524 [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 Res127:195–207 [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. Blood105:3605–3614 [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 Virol82:3466–3479 [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. Hepatology34:1206–1217 [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. Hepatology40:1062–1071 [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 Immunol38:2665–2677 [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. Hepatology42:104–112 [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 Immunol203:111–123 [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 Res16:5852–5861 [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 Ther10:686–699 [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 Ther11:522–533 [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. Vaccine26:3818–3826 [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 Dis187:1951–1958 [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 Virol76:12735–12746 [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 Cancer81:979–984 [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 Lett85:165–171 [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 Invest118:1143–1153[PubMed]
    [Google Scholar]
  25. Kieback E., Uckert W.. 2010; Enhanced T cell receptor gene therapy for cancer. Expert Opin Biol Ther10:749–762 [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 Immunol36:2046–2060 [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 Immunol30:2479–2487 [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 Med3:35 [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 Immunol186:901–912 [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. Hepatology44:945–954 [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. Hepatology48:713–722 [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 Hepat6:Suppl. 136–40 [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 Med185:2043–2051 [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 Virol81:2545–2553 [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 Surveill13:pii: 18880[PubMed]
    [Google Scholar]
  36. Rock K. L., Rothstein L., Gamble S.. 1990; Generation of class I MHC-restricted T-T hybridomas. J Immunol145:804–811[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 Immunol170:2582–2589[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 Immunol175:3603–3613[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. Gut55:266–274 [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. Hepatology38:1437–1448[PubMed]
    [Google Scholar]
  41. Thompson A. J., McHutchison J. G.. 2009; Review article: investigational agents for chronic hepatitis C. Aliment Pharmacol Ther29:689–705 [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 Immunol6:883–894 [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. Hepatology41:643–651 [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 Med201:675–680 [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 Virol75:11392–11400 [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 Immunol169:3447–3458[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. Hepatology37:577–589 [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. Hepatology45:1422–1432 [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 Pathog6: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...

Most cited this month Most Cited RSS feed

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