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How not to be seen: immune-evasion strategies in gene therapy

Gene Therapy volume 15, pages 239–246 (2008)Cite this article

Abstract

The development of efficient and safe vectors for gene delivery paved the way for evolution of gene therapy as a new modality for treatment of various inherited disorders and for cancer. The current vectors, viral and non-viral, have their limitations. Innate and adaptive immune responses to vector particles and components may restrict the efficiency of gene transfer and the persistence of expression of the transgene. Results from preclinical studies in animals and more recently data from clinical studies have demonstrated the potential impact of the cellular and the humoral immune response on the therapeutic efficacy. Not only the vector components, but also the transgene products may induce an immune response that negatively affects the therapeutic efficacy. The induction of a cytotoxic T-cell response to transgene-encoded peptides, as well as the production of antibodies directed against secreted proteins have been reported in preclinical and clinical studies, and these may thwart those applications that require long-term expression. Here we will review some of the options to blunt the acquired immune responses to transgene-encoded polypeptides.

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References

  1. Bittner RE, Shorny S, Streubel B, Hubner C, Voit T, Kress W . Serum antibodies to the deleted dystrophin sequence after cardiac transplantation in a patient with Becker's muscular dystrophy. N Engl J Med 1995; 333: 732–733.

    Article  CAS  PubMed  Google Scholar 

  2. Tremblay JP, Malouin F, Roy R, Huard J, Bouchard JP, Satoh A et al. Results of a triple blind clinical study of myoblast transplantations without immunosuppressive treatment in young boys with Duchenne muscular dystrophy. Cell Transplant 1993; 2: 99–112.

    Article  CAS  PubMed  Google Scholar 

  3. Ferrer A, Wells KE, Wells DJ . Immune responses to dystropin: implications for gene therapy of Duchenne muscular dystrophy. Gene Therapy 2000; 7: 1439–1446.

    Article  CAS  PubMed  Google Scholar 

  4. Yuasa K, Sakamoto M, Miyagoe-Suzuki Y, Tanouchi A, Yamamoto H, Li J et al. Adeno-associated virus vector-mediated gene transfer into dystrophin-deficient skeletal muscles evokes enhanced immune response against the transgene product. Gene Therapy 2002; 9: 1576–1588.

    Article  CAS  PubMed  Google Scholar 

  5. Figueredo J, Limberis M, Wilson JM . Prediction of cellular immune responses against CFTR in cystic fibrosis patients after gene therapy. Am J Respir Cell Mol Biol 2007; 36: 529–533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pulkkanen KJ, Parkkinen JJ, Laukkanen JM, Kettunen MI, Tyynela K, Kauppinen RA et al. HSV-tk gene therapy for human renal cell carcinoma in nude mice. Cancer Gene Ther 2001; 8: 529–536.

    Article  CAS  PubMed  Google Scholar 

  7. Pulkkanen KJ, Laukkanen JM, Fuxe J, Kettunen MI, Rehn M, Kannasto JM et al. The combination of HSV-tk and endostatin gene therapy eradicates orthotopic human renal cell carcinomas in nude mice. Cancer Gene Ther 2002; 9: 908–916.

    Article  CAS  PubMed  Google Scholar 

  8. Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 1997; 276: 1719–1724.

    Article  CAS  PubMed  Google Scholar 

  9. Bonini C, Ciceri F, Marktel S, Bordignon C . Suicide-gene-transduced T-cells for the regulation of the graft-versus-leukemia effect. Vox Sang 1998; 74 (Suppl 2): 341–343.

    Article  CAS  PubMed  Google Scholar 

  10. Traversari C, Marktel S, Magnani Z, Mangia P, Russo V, Ciceri F et al. The potential immunogenicity of the TK suicide gene does not prevent full clinical benefit associated with the use of TK-transduced donor lymphocytes in HSCT for hematologic malignancies. Blood 2007; 109: 4708–4715.

    Article  CAS  PubMed  Google Scholar 

  11. Latta-Mahieu M, Rolland M, Caillet C, Wang M, Kennel P, Mahfouz I et al. Gene transfer of a chimeric trans-activator is immunogenic and results in short-lived transgene expression. Hum Gene Ther 2002; 13: 1611–1620.

    Article  CAS  PubMed  Google Scholar 

  12. Hanazono Y, Terao K, Shibata H, Nagashima T, Ageyama N, Asano T et al. Introduction of the green fluorescent protein gene into hematopoietic stem cells results in prolonged discrepancy of in vivo transduction levels between bone marrow progenitors and peripheral blood cells in nonhuman primates. J Gene Med 2002; 4: 470–477.

    Article  CAS  PubMed  Google Scholar 

  13. Moens U, Mathiesen I, Ghelue MV, Rekvig OP . Green fluorescent protein modified to bind DNA initiates production of anti-DNA antibodies when expressed in vivo. Mol Immunol 2002; 38: 505–514.

    Article  CAS  PubMed  Google Scholar 

  14. Rosenzweig M, Connole M, Glickman R, Yue SP, Noren B, DeMaria M et al. Induction of cytotoxic T lymphocyte and antibody responses to enhanced green fluorescent protein following transplantation of transduced CD34(+) hematopoietic cells. Blood 2001; 97: 1951–1959.

    Article  CAS  PubMed  Google Scholar 

  15. Stripecke R, Carmen VM, Skelton D, Satake N, Halene S, Kohn D . Immune response to green fluorescent protein: implications for gene therapy. Gene Therapy 1999; 6: 1305–1312.

    Article  CAS  PubMed  Google Scholar 

  16. Snyder RO, Miao C, Meuse L, Tubb J, Donahue BA, Lin HF et al. Correction of hemophilia B in canine and murine models using recombinant adeno-associated viral vectors. Nat Med 1999; 5: 64–70.

    Article  CAS  PubMed  Google Scholar 

  17. Ge Y, Powell S, Van Roey M, McArthur JG . Factors influencing the development of an anti-factor IX (FIX) immune response following administration of adeno-associated virus-FIX. Blood 2001; 97: 3733–3737.

    Article  CAS  PubMed  Google Scholar 

  18. Mount JD, Herzog RW, Tillson DM, Goodman SA, Robinson N, McCleland ML et al. Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy. Blood 2002; 99: 2670–2676.

    Article  CAS  PubMed  Google Scholar 

  19. Follenzi A, Battaglia M, Lombardo A, Annoni A, Roncarolo MG, Naldini L . Targeting lentiviral vector expression to hepatocytes limits transgene-specific immune response and establishes long-term expression of human antihemophilic factor IX in mice. Blood 2004; 103: 3700–3709.

    Article  CAS  PubMed  Google Scholar 

  20. Zhou S, Murphy JE, Escobedo JA, Dwarki VJ . Adeno-associated virus-mediated delivery of erythropoietin leads to sustained elevation of hematocrit in nonhuman primates. Gene Therapy 1998; 5: 665–670.

    Article  CAS  PubMed  Google Scholar 

  21. Kessler PD, Podsakoff GM, Chen X, McQuiston SA, Colosi PC, Matelis LA et al. Gene delivery to skeletal muscle results in sustained expression and systemic delivery of a therapeutic protein. Proc Natl Acad Sci USA 1996; 93: 14082–14087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rinsch C, Dupraz P, Schneider BL, Deglon N, Maxwell PH, Ratcliffe PJ et al. Delivery of erythropoietin by encapsulated myoblasts in a genetic model of severe anemia. Kidney Int 2002; 62: 1395–1401.

    Article  CAS  PubMed  Google Scholar 

  23. Gao G, Lebherz C, Weiner DJ, Grant R, Calcedo R, McCullough B et al. Erythropoietin gene therapy leads to autoimmune anemia in macaques. Blood 2004; 103: 3300–3302.

    Article  CAS  PubMed  Google Scholar 

  24. Hughes V . Therapy on trial. Nat Med 2007; 13: 1008–1009.

    Article  CAS  PubMed  Google Scholar 

  25. Schagen FH, Ossevoort M, Toes RE, Hoeben RC . Immune responses against adenoviral vectors and their transgene products: a review of strategies for evasion. Crit Rev Oncol Hematol 2004; 50: 51–70.

    Article  PubMed  Google Scholar 

  26. Fields PA, Kowalczyk DW, Arruda VR, Armstrong E, McCleland ML, Hagstrom JN et al. Role of vector in activation of T cell subsets in immune responses against the secreted transgene product factor IX. Mol Ther 2000; 1: 225–235.

    Article  CAS  PubMed  Google Scholar 

  27. Jooss K, Yang Y, Fisher KJ, Wilson JM . Transduction of dendritic cells by DNA viral vectors directs the immune response to transgene products in muscle fibers. J Virol 1998; 72: 4212–4223.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Dow SW, Fradkin LG, Liggitt DH, Willson AP, Heath TD, Potter TA . Lipid-DNA complexes induce potent activation of innate immune responses and antitumor activity when administered intravenously. J Immunol 1999; 163: 1552–1561.

    CAS  PubMed  Google Scholar 

  29. Whitmore M, Li S, Huang L . LPD lipopolyplex initiates a potent cytokine response and inhibits tumor growth. Gene Therapy 1999; 6: 1867–1875.

    Article  CAS  PubMed  Google Scholar 

  30. Akira S, Uematsu S, Takeuchi O . Pathogen recognition and innate immunity. Cell 2006; 124: 783–801.

    Article  CAS  PubMed  Google Scholar 

  31. Zhu J, Huang X, Yang Y . Innate immune response to adenoviral vectors is mediated by both Toll-like receptor-dependent and -independent pathways. J Virol 2007; 81: 3170–3180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Stack J, Haga IR, Schroder M, Bartlett NW, Maloney G, Reading PC et al. Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence. J Exp Med 2005; 201: 1007–1018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Abe T, Kaname Y, Hamamoto I, Tsuda Y, Wen X, Taguwa S et al. Hepatitis C virus nonstructural protein 5A modulates the toll-like receptor-MyD88-dependent signaling pathway in macrophage cell lines. J Virol 2007; 81: 8953–8966.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Foy E, Li K, Sumpter Jr R, Loo YM, Johnson CL, Wang C et al. Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. Proc Natl Acad Sci USA 2005; 102: 2986–2991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yu Y, Wang SE, Hayward GS . The KSHV immediate-early transcription factor RTA encodes ubiquitin E3 ligase activity that targets IRF7 for proteosome-mediated degradation. Immunity 2005; 22: 59–70.

    Article  CAS  PubMed  Google Scholar 

  36. Ikezawa Y, Nakazawa M, Tamura C, Takahashi K, Minami M, Ikezawa Z . Cyclophosphamide decreases the number, percentage and the function of CD25+ CD4+ regulatory T cells, which suppress induction of contact hypersensitivity. J Dermatol Sci 2005; 39: 105–112.

    Article  CAS  PubMed  Google Scholar 

  37. Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H . Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 2005; 105: 2862–2868.

    Article  CAS  PubMed  Google Scholar 

  38. Thomson AW, Bonham CA, Zeevi A . Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit 1995; 17: 584–591.

    Article  CAS  PubMed  Google Scholar 

  39. Judge TA, Tang A, Turka LA . Immunosuppression through blockade of CD28:B7-mediated costimulatory signals. Immunol Res 1996; 15: 38–49.

    Article  CAS  PubMed  Google Scholar 

  40. Lenschow DJ, Su GH, Zuckerman LA, Nabavi N, Jellis CL, Gray GS et al. Expression and functional significance of an additional ligand for CTLA-4. Proc Natl Acad Sci USA 1993; 90: 11054–11058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kay MA, Holterman AX, Meuse L, Gown A, Ochs HD, Linsley PS et al. Long-term hepatic adenovirus-mediated gene expression in mice following CTLA4Ig administration. Nat Genet 1995; 11: 191–197.

    Article  CAS  PubMed  Google Scholar 

  42. Feng S, Quickel RR, Hollister-Lock J, McLeod M, Bonner-Weir S, Mulligan RC et al. Prolonged xenograft survival of islets infected with small doses of adenovirus expressing CTLA4Ig. Transplantation 1999; 67: 1607–1613.

    Article  CAS  PubMed  Google Scholar 

  43. Fernandes JR, Duvivier-Kali VF, Keegan M, Hollister-Lock J, Omer A, Su S et al. Transplantation of islets transduced with CTLA4-Ig and TGFbeta using adenovirus and lentivirus vectors. Transpl Immunol 2004; 13: 191–200.

    Article  CAS  PubMed  Google Scholar 

  44. Miao CH, Ye P, Thompson AR, Rawlings DJ, Ochs HD . Immunomodulation of transgene responses following naked DNA transfer of human factor VIII into hemophilia A mice. Blood 2006; 108: 19–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bickerstaff AA, Wang JJ, Xia D, Orosz CG . Allograft acceptance despite differential strain-specific induction of TGF-beta/IL-10-mediated immunoregulation. Am J Transplant 2002; 2: 819–827.

    Article  CAS  PubMed  Google Scholar 

  46. Ranges GE, Figari IS, Espevik T, Palladino MA, Jr. Inhibition of cytotoxic T cell development by transforming growth factor beta and reversal by recombinant tumor necrosis factor alpha. J Exp Med 1987; 166: 991–998.

    Article  CAS  PubMed  Google Scholar 

  47. Bejarano MT, de Waal MR, Abrams JS, Bigler M, Bacchetta R, de Vries JE et al. Interleukin 10 inhibits allogeneic proliferative and cytotoxic T cell responses generated in primary mixed lymphocyte cultures. Int Immunol 1992; 4: 1389–1397.

    Article  CAS  PubMed  Google Scholar 

  48. Zuo Z, Wang C, Carpenter D, Okada Y, Nicolaidou E, Toyoda M et al. Prolongation of allograft survival with viral IL-10 transfection in a highly histoincompatible model of rat heart allograft rejection. Transplantation 2001; 71: 686–691.

    Article  CAS  PubMed  Google Scholar 

  49. Carter JD, Ellett JD, Chen M, Smith KM, Fialkow LB, McDuffie MJ et al. Viral IL-10-mediated immune regulation in pancreatic islet transplantation. Mol Ther 2005; 12: 360–368.

    Article  CAS  PubMed  Google Scholar 

  50. Yang Z, Chen M, Wu R, Fialkow LB, Bromberg JS, McDuffie M et al. Suppression of autoimmune diabetes by viral IL-10 gene transfer. J Immunol 2002; 168: 6479–6485.

    Article  CAS  PubMed  Google Scholar 

  51. Wolf D, Wolf AM, Rumpold H, Fiegl H, Zeimet AG, Muller-Holzner E et al. The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin Cancer Res 2005; 11: 8326–8331.

    Article  CAS  PubMed  Google Scholar 

  52. Wood KJ, Sakaguchi S . Regulatory T cells in transplantation tolerance. Nat Rev Immunol 2003; 3: 199–210.

    Article  CAS  PubMed  Google Scholar 

  53. Lan RY, Ansari AA, Lian ZX, Gershwin ME . Regulatory T cells: development, function and role in autoimmunity. Autoimmun Rev 2005; 4: 351–363.

    Article  CAS  PubMed  Google Scholar 

  54. Battaglia M, Stabilini A, Draghici E, Migliavacca B, Gregori S, Bonifacio E et al. Induction of tolerance in type 1 diabetes via both CD4+CD25+ T regulatory cells and T regulatory type 1 cells. Diabetes 2006; 55: 1571–1580.

    Article  CAS  PubMed  Google Scholar 

  55. Tarbell KV, Petit L, Zuo X, Toy P, Luo X, Mqadmi A et al. Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J Exp Med 2007; 204: 191–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ziegler RJ, Lonning SM, Armentano D, Li C, Souza DW, Cherry M et al. AAV2 vector harboring a liver-restricted promoter facilitates sustained expression of therapeutic levels of alpha-galactosidase A and the induction of immune tolerance in Fabry mice. Mol Ther 2004; 9: 231–240.

    Article  CAS  PubMed  Google Scholar 

  57. Mingozzi F, Liu YL, Dobrzynski E, Kaufhold A, Liu JH, Wang Y et al. Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer. J Clin Invest 2003; 111: 1347–1356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Dobrzynski E, Herzog RW . Tolerance induction by viral in vivo gene transfer. Clin Med Res 2005; 3: 234–240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Dobrzynski E, Fitzgerald JC, Cao O, Mingozzi F, Wang L, Herzog RW . Prevention of cytotoxic T lymphocyte responses to factor IX-expressing hepatocytes by gene transfer-induced regulatory T cells. Proc Natl Acad Sci USA 2006; 103: 4592–4597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cao O, Dobrzynski E, Wang L, Nayak S, Mingle B, Terhorst C et al. Induction and role of regulatory CD4+CD25+ T cells in tolerance to the transgene product following hepatic in vivo gene transfer. Blood 2007; 110: 1132–1140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Carlotti F, Zaldumbide A, Martin P, Boulukos KE, Hoeben RC, Pognonec P . Development of an inducible suicide gene system based on human caspase 8. Cancer Gene Ther 2005; 12: 627–639.

    Article  CAS  PubMed  Google Scholar 

  62. Thomis DC, Marktel S, Bonini C, Traversari C, Gilman M, Bordignon C et al. A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease. Blood 2001; 97: 1249–1257.

    Article  CAS  PubMed  Google Scholar 

  63. Serafini M, Manganini M, Borleri G, Bonamino M, Imberti L, Biondi A et al. Characterization of CD20-transduced T lymphocytes as an alternative suicide gene therapy approach for the treatment of graft-versus-host disease. Hum Gene Ther 2004; 15: 63–76.

    Article  CAS  PubMed  Google Scholar 

  64. Brown BD, Shi CX, Rawle FE, Tinlin S, McKinven A, Hough C et al. Factors influencing therapeutic efficacy and the host immune response to helper-dependent adenoviral gene therapy in hemophilia A mice. J Thromb Haemost 2004; 2: 111–118.

    Article  CAS  PubMed  Google Scholar 

  65. Rana TM . Illuminating the silence: understanding the structure and function of small RNAs. Nat Rev Mol Cell Biol 2007; 8: 23–36.

    Article  CAS  PubMed  Google Scholar 

  66. Brown BD, Venneri MA, Zingale A, Sergi SL, Naldini L . Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer. Nat Med 2006; 12: 585–591.

    Article  CAS  PubMed  Google Scholar 

  67. Brown BD, Cantore A, Annoni A, Sergi SL, Lombardo A, Della VP et al. A microRNA-regulated lentiviral vector mediates stable correction of hemophilia B mice. Blood 2007 [E-pub ahead of print; doi:10.1182/blood-2007-03-078493].

  68. Loenen WA, Bruggeman CA, Wiertz EJ . Immune evasion by human cytomegalovirus: lessons in immunology and cell biology. Semin Immunol 2001; 13: 41–49.

    Article  CAS  PubMed  Google Scholar 

  69. Vossen MT, Westerhout EM, Soderberg-Naucler C, Wiertz EJ . Viral immune evasion: a masterpiece of evolution. Immunogenetics 2002; 54: 527–542.

    Article  CAS  PubMed  Google Scholar 

  70. Wiertz EJ, Tortorella D, Bogyo M, Yu J, Mothes W, Jones TR et al. Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 1996; 384: 432–438.

    Article  CAS  PubMed  Google Scholar 

  71. Wiertz EJ, Jones TR, Sun L, Bogyo M, Geuze HJ, Ploegh HL . The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell 1996; 84: 769–779.

    Article  CAS  PubMed  Google Scholar 

  72. Ahn K, Angulo A, Ghazal P, Peterson PA, Yang Y, Fruh K . Human cytomegalovirus inhibits antigen presentation by a sequential multistep process. Proc Natl Acad Sci USA 1996; 93: 10990–10995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Coscoy L, Ganem D . Kaposi's sarcoma-associated herpesvirus encodes two proteins that block cell surface display of MHC class I chains by enhancing their endocytosis. Proc Natl Acad Sci USA 2000; 97: 8051–8056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Edelman DC . Human herpesvirus 8--a novel human pathogen. Virol J 2005; 2: 78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Greenberg ME, Iafrate AJ, Skowronski J . The SH3 domain-binding surface and an acidic motif in HIV-1 Nef regulate trafficking of class I MHC complexes. EMBO J 1998; 17: 2777–2789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Le Gall S, Buseyne F, Trocha A, Walker BD, Heard JM, Schwartz O . Distinct trafficking pathways mediate Nef-induced and clathrin-dependent major histocompatibility complex class I down-regulation. J Virol 2000; 74: 9256–9266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Koppers-Lalic D, Reits EA, Ressing ME, Lipinska AD, Abele R, Koch J et al. Varicelloviruses avoid T cell recognition by UL49.5-mediated inactivation of the transporter associated with antigen processing. Proc Natl Acad Sci USA 2005; 102: 5144–5149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Tomazin R, Hill AB, Jugovic P, York I, van Endert P, Ploegh HL et al. Stable binding of the herpes simplex virus ICP47 protein to the peptide binding site of TAP. EMBO J 1996; 15: 3256–3266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lehner PJ, Karttunen JT, Wilkinson GW, Cresswell P . The human cytomegalovirus US6 glycoprotein inhibits transporter associated with antigen processing-dependent peptide translocation. Proc Natl Acad Sci USA 1997; 94: 6904–6909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Berger C, Xuereb S, Johnson DC, Watanabe KS, Kiem HP, Greenberg PD et al. Expression of herpes simplex virus ICP47 and human cytomegalovirus US11 prevents recognition of transgene products by CD8(+) cytotoxic T lymphocytes. J Virol 2000; 74: 4465–4473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Furukawa L, Brevetti LS, Brady SE, Johnson D, Ma M, Welling TH et al. Adenoviral-mediated gene transfer of ICP47 inhibits major histocompatibility complex class I expression on vascular cells in vitro. J Vasc Surg 2000; 31: 558–566.

    Article  CAS  PubMed  Google Scholar 

  82. Ayalon O, Hughes EA, Cresswell P, Lee J, O'Donnell L, Pardi R et al. Induction of transporter associated with antigen processing by interferon gamma confers endothelial cell cytoprotection against natural killer-mediated lysis. Proc Natl Acad Sci USA 1998; 95: 2435–2440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Huard B, Fruh K . A role for MHC class I down-regulation in NK cell lysis of herpes virus-infected cells. Eur J Immunol 2000; 30: 509–515.

    Article  CAS  PubMed  Google Scholar 

  84. Scaria A, Sullivan JA, St George JA, Kaplan JM, Lukason MJ, Morris JE et al. Adenoviral vector expressing ICP47 inhibits adenovirus-specific cytotoxic T lymphocytes in nonhuman primates. Mol Ther 2000; 2: 505–514.

    Article  CAS  PubMed  Google Scholar 

  85. von Herrath MG, Efrat S, Oldstone MB, Horwitz MS . Expression of adenoviral E3 transgenes in beta cells prevents autoimmune diabetes. Proc Natl Acad Sci USA 1997; 94: 9808–9813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Levitskaya J, Coram M, Levitsky V, Imreh S, Steigerwald-Mullen PM, Klein G et al. Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature 1995; 375: 685–688.

    Article  CAS  PubMed  Google Scholar 

  87. Levitskaya J, Sharipo A, Leonchiks A, Ciechanover A, Masucci MG . Inhibition of ubiquitin/proteasome-dependent protein degradation by the Gly-Ala repeat domain of the Epstein-Barr virus nuclear antigen 1. Proc Natl Acad Sci USA 1997; 94: 12616–12621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ossevoort M, Zaldumbide A, Cramer SJ, van der Voort EI, Toes RE, Hoeben RC . Characterization of an immuno ‘stealth’ derivative of the herpes simplex virus thymidine-kinase gene. Cancer Gene Ther 2006; 13: 584–591.

    Article  CAS  PubMed  Google Scholar 

  89. Ossevoort M, Visser BM, van den Wollenberg DJ, van der Voort EI, Offringa R, Melief CJ et al. Creation of immune ‘stealth’ genes for gene therapy through fusion with the Gly-Ala repeat of EBNA-1. Gene Therapy 2003; 10: 2020–2028.

    Article  CAS  PubMed  Google Scholar 

  90. Tellam J, Sherritt M, Thomson S, Tellam R, Moss DJ, Burrows SR et al. Targeting of EBNA1 for rapid intracellular degradation overrides the inhibitory effects of the Gly-Ala repeat domain and restores CD8+ T cell recognition. J Biol Chem 2001; 276: 33353–33360.

    Article  CAS  PubMed  Google Scholar 

  91. Yewdell JW, Schubert U, Bennink JR . At the crossroads of cell biology and immunology: DRiPs and other sources of peptide ligands for MHC class I molecules. J Cell Sci 2001; 114: 845–851.

    CAS  PubMed  Google Scholar 

  92. Yewdell JW, Nicchitta CV . The DRiP hypothesis decennial: support, controversy, refinement and extension. Trends Immunol 2006; 27: 368–373.

    Article  CAS  PubMed  Google Scholar 

  93. Ossevoort M, Zaldumbide A, Te Velthuis AJ, Melchers M, Ressing ME, Wiertz EJ et al. The nested open reading frame in the Epstein-Barr virus nuclear antigen-1 mRNA encodes a protein capable of inhibiting antigen presentation in cis. Mol Immunol 2007; 44: 3588–3596.

    Article  CAS  PubMed  Google Scholar 

  94. Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 2006; 12: 342–347.

    Article  CAS  PubMed  Google Scholar 

  95. Mount JD, Herzog RW, Tillson DM, Goodman SA, Robinson N, McCleland ML et al. Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy. Blood 2002; 99: 2670–2676.

    Article  CAS  PubMed  Google Scholar 

  96. Wang L, Nichols TC, Read MS, Bellinger DA, Verma IM . Sustained expression of therapeutic level of factor IX in hemophilia B dogs by AAV-mediated gene therapy in liver. Mol Ther 2000; 1: 154–158.

    Article  CAS  PubMed  Google Scholar 

  97. Mingozzi F, Maus MV, Hui DJ, Sabatino DE, Murphy SL, Rasko JE et al. CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nat Med 2007; 13: 419–422.

    Article  CAS  PubMed  Google Scholar 

  98. Mingozzi F, Hasbrouck NC, Basner-Tschkarajan E, Edmonson SA, Hui DJ, Sabatino DE et al. Modulation of tolerance to the transgene product in a non-human primate model of AAV-mediated gene transfer to liver. Blood 2007: 2334–2341.

  99. Zaldumbide A, Ossevoort M, Wiertz EJ, Hoeben RC . In cis inhibition of antigen processing by the latency-associated nuclear antigen I of Kaposi sarcoma herpes virus. Mol Immunol 2007; 44: 1352–1360.

    Article  CAS  PubMed  Google Scholar 

  100. Kwun HJ, da Silva SR, Shah IM, Blake N, Moore PS, Chang Y . Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen 1 mimics Epstein-Barr virus EBNA1 immune evasion through central repeat domain effects on protein processing. J Virol 2007; 81: 8225–8235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Bennett NJ, May JS, Stevenson PG . Gamma-herpesvirus latency requires T cell evasion during episome maintenance. PLoS Biol 2005; 3: e120.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Sharipo A, Imreh M, Leonchiks A, Branden C, Masucci MG . cis-Inhibition of proteasomal degradation by viral repeats: impact of length and amino acid composition. FEBS Lett 2001; 499: 137–142.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Françoise Carlotti, Dr Danijela Koppers-Lalic and Dr Twan de Vries for critical reading of the paper. This work was supported by the European Union through the 6th Framework Program GIANT (Contract no.: 512087), and by Diabetes Research Fund (DFN 2005.00.0212).

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  1. Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands

    A Zaldumbide & R C Hoeben

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Zaldumbide, A., Hoeben, R. How not to be seen: immune-evasion strategies in gene therapy. Gene Ther 15, 239–246 (2008). https://doi.org/10.1038/sj.gt.3303082

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