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Abstract

Hepatitis C virus (HCV) readily establishes chronic infection, which is characterized by failure of virus-specific CD8 T cells. HCV uses epitope mutation and T-cell exhaustion to escape from the host immune response. Previously, we engineered high-affinity T-cell receptors (HATs) targeting human immunodeficiency virus escape mutants. In this study, the affinity of a T-cell receptor specific for the HLA-A2-restricted HCV immunodominant epitope NS3 1406–1415 (KLVALGINAV) was improved from a K of 6.6 µM to 40 pM. These HATs could also target HCV NS3 naturally occurring variants, including an escape variant vrt1 (KLVVLGINAV), with high affinities. The HATs can be used as high-affinity targeting molecules at the centre of the immune synapse for the HLA-restricted NS3 antigen. By fusing the HAT with a T-cell activation molecule, an anti-CD3 single-chain variable fragment, we constructed a molecule called high-affinity T-cell activation core (HATac), which can redirect functional CTLs possessing any specificity to recognize and kill cells presenting HCV NS3 antigens. This capability was verified with T2 cells loaded with prototype or variant peptides and HepG2 cells expressing the truncated NS3 prototype or variant proteins. The results indicate that HATac targeting the HLA-restricted NS3 antigen may provide a useful tool for circumventing immune escape mutants and T-cell exhaustion caused by HCV infection.

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2017-03-01
2024-03-29
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References

  1. Centers for Disease Control and Prevention 2012; Hepatitis C information for the public. www.cdc.gov/hepatitis/C/cFAQ.htm#statistics
  2. World Health Organization Prevention & control of viral hepatitis infection: Framework for global action. World Health Organization 2012
  3. Gogela NA, Lin MV, Wisocky JL, Chung RT. Enhancing our understanding of current therapies for hepatitis C virus (HCV). Curr HIV/AIDS Rep 2015; 12:68–78 [View Article]
    [Google Scholar]
  4. Chayama K, Hayes CN. HCV drug resistance challenges in Japan: the role of pre-existing variants and emerging resistant strains in direct acting antiviral therapy. Viruses 2015; 7:5328–5342 [View Article][PubMed]
    [Google Scholar]
  5. Poveda E, Wyles DL, Mena A, Pedreira JD, Castro-Iglesias A et al. Update on hepatitis C virus resistance to direct-acting antiviral agents. Antiviral Res 2014; 108:181–191 [View Article][PubMed]
    [Google Scholar]
  6. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 2005; 5:215–229 [View Article][PubMed]
    [Google Scholar]
  7. Thimme R, Oldach D, Chang KM, Steiger C, Ray SC et al. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med 2001; 194:1395–1406[PubMed] [Crossref]
    [Google Scholar]
  8. Cox AL, Mosbruger T, Lauer GM, Pardoll D, Thomas DL et al. Comprehensive analyses of CD8+ T cell responses during longitudinal study of acute human hepatitis C. Hepatology 2005; 42:104–112 [View Article][PubMed]
    [Google Scholar]
  9. Cox AL, Mosbruger T, Mao Q, Liu Z, Wang XH et al. Cellular immune selection with hepatitis C virus persistence in humans. J Exp Med 2005; 201:1741–1752 [View Article][PubMed]
    [Google Scholar]
  10. Merani S, Petrovic D, James I, Chopra A, Cooper D et al. Effect of immune pressure on Hepatitis C virus evolution: insights from a single-source outbreak. Hepatology 2011; 53:396–405 [View Article][PubMed]
    [Google Scholar]
  11. Tester I, Smyk-Pearson S, Wang P, Wertheimer A, Yao E et al. Immune evasion versus recovery after acute hepatitis C virus infection from a shared source. J Exp Med 2005; 201:1725–1731 [View Article][PubMed]
    [Google Scholar]
  12. Ulsenheimer A, Paranhos-Baccalà G, Komurian-Pradel F, Raziorrouh B, Kurktschiev P et al. Lack of variant specific CD8+ T-cell response against mutant and pre-existing variants leads to outgrowth of particular clones in acute hepatitis C. Virol J 2013; 10:295 [View Article][PubMed]
    [Google Scholar]
  13. Wölfl M, Rutebemberwa A, Mosbruger T, Mao Q, Li HM et al. Hepatitis C virus immune escape via exploitation of a hole in the T cell repertoire. J Immunol 2008; 181:6435–6446[PubMed] [Crossref]
    [Google Scholar]
  14. Klenerman P, Thimme R. T cell responses in hepatitis C: the good, the bad and the unconventional. Gut 2012; 61:1226–1234 [View Article][PubMed]
    [Google Scholar]
  15. Wherry EJ. T cell exhaustion. Nat Immunol 2011; 12:492–499[PubMed] [Crossref]
    [Google Scholar]
  16. Bengsch B, Seigel B, Ruhl M, Timm J, Kuntz M et al. Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation. PLoS Pathog 2010; 6:e1000947 [View Article][PubMed]
    [Google Scholar]
  17. Nitschke K, Flecken T, Schmidt J, Gostick E, Marget M et al. Tetramer enrichment reveals the presence of phenotypically diverse hepatitis C virus-specific CD8+ T cells in chronic infection. J Virol 2015; 89:25–34 [View Article][PubMed]
    [Google Scholar]
  18. Penna A, Pilli M, Zerbini A, Orlandini A, Mezzadri S et al. Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection. Hepatology 2007; 45:588–601 [View Article][PubMed]
    [Google Scholar]
  19. Dustin ML, Depoil D. New insights into the T cell synapse from single molecule techniques. Nat Rev Immunol 2011; 11:672–684 [View Article][PubMed]
    [Google Scholar]
  20. Manz BN, Jackson BL, Petit RS, Dustin ML, Groves J. T-cell triggering thresholds are modulated by the number of antigen within individual T-cell receptor clusters. Proc Natl Acad Sci USA 2011; 108:9089–9094 [View Article][PubMed]
    [Google Scholar]
  21. Li Y, Moysey R, Molloy PE, Vuidepot AL, Mahon T et al. Directed evolution of human T-cell receptors with picomolar affinities by phage display. Nat Biotechnol 2005; 23:349–354 [View Article][PubMed]
    [Google Scholar]
  22. Liddy N, Bossi G, Adams KJ, Lissina A, Mahon TM et al. Monoclonal TCR-redirected tumor cell killing. Nat Med 2012; 18:980–987 [View Article][PubMed]
    [Google Scholar]
  23. Varela-Rohena A, Molloy PE, Dunn SM, Li Y, Suhoski MM et al. Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor. Nat Med 2008; 14:1390–1395 [View Article][PubMed]
    [Google Scholar]
  24. Callender GG, Rosen HR, Roszkowski JJ, Lyons GE, Li M et al. Identification of a hepatitis C virus-reactive T cell receptor that does not require CD8 for target cell recognition. Hepatology 2006; 43:973–981 [View Article][PubMed]
    [Google Scholar]
  25. Rosen HR, Hinrichs DJ, Leistikow RL, Callender G, Wertheimer AM et al. Cutting edge: identification of hepatitis C virus-specific CD8+ T cells restricted by donor HLA alleles following liver transplantation. J Immunol 2004; 173:5355–5359[PubMed] [Crossref]
    [Google Scholar]
  26. Boulter JM, Glick M, Todorov PT, Baston E, Sami M et al. Stable, soluble T-cell receptor molecules for crystallization and therapeutics. Protein Eng 2003; 16:707–711[PubMed] [Crossref]
    [Google Scholar]
  27. Cole DK, Pumphrey NJ, Boulter JM, Sami M, Bell JI et al. Human TCR-binding affinity is governed by MHC class restriction. J Immunol 2007; 178:5727–5734[PubMed] [Crossref]
    [Google Scholar]
  28. Timm J, Walker CM. Mutational escape of CD8+ T cell epitopes: implications for prevention and therapy of persistent hepatitis virus infections. Med Microbiol Immunol 2015; 204:29–38 [View Article][PubMed]
    [Google Scholar]
  29. Giugliano S, Oezkan F, Bedrejowski M, Kudla M, Reiser M et al. Degree of cross-genotype reactivity of hepatitis C virus-specific CD8+ T cells directed against NS3. H epatology 2009; 50:707–716 [View Article][PubMed]
    [Google Scholar]
  30. Ziegler S, Skibbe K, Walker A, Ke X, Heinemann FM et al. Impact of sequence variation in a dominant HLA-A*02-restricted epitope in Hepatitis C virus on priming and cross-reactivity of CD8+ T cells. J Virol 2014; 88:11080–11090 [View Article][PubMed]
    [Google Scholar]
  31. Pasetto A, Aleman S, Chen M. Functional attributes of responding T cells in HCV infection: the recent advances in engineering functional antiviral T cells. Arch Immunol Ther Exp 2014; 62:23–30 [View Article][PubMed]
    [Google Scholar]
  32. Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015; 348:62–68 [View Article][PubMed]
    [Google Scholar]
  33. Heslop HE, Slobod KS, Pule MA, Hale GA, Rousseau A et al. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood 2010; 115:925–935 [View Article][PubMed]
    [Google Scholar]
  34. Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 1995; 333:1038–1044 [View Article][PubMed]
    [Google Scholar]
  35. Feuchtinger T, Matthes-Martin S, Richard C, Lion T, Fuhrer M et al. Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation. Br J Haematol 2006; 134:64–76 [View Article][PubMed]
    [Google Scholar]
  36. Balduzzi A, Lucchini G, Hirsch HH, Basso S, Cioni M et al. Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient. Bone Marrow Transplant 2011; 46:987–992 [View Article][PubMed]
    [Google Scholar]
  37. Oates J, Hassan NJ, Jakobsen BK. ImmTACs for targeted cancer therapy: why, what, how, and which. Mol Immunol 2015; 67:67–74 [View Article][PubMed]
    [Google Scholar]
  38. Blight KJ, Mckeating JA, Marcotrigiano J, Rice CM. Efficient replication of hepatitis C virus genotype 1a RNAs in cell culture. J Virol 2003; 77:3181–3190[PubMed] [Crossref]
    [Google Scholar]
  39. Garboczi DN, Hung DT, Wiley DC. HLA-A2-peptide complexes: refolding and crystallization of molecules expressed in Escherichia coli and complexed with single antigenic peptides. Proc Natl Acad Sci USA 1992; 89:3429–3433[PubMed] [Crossref]
    [Google Scholar]
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