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Immune responses to adeno-associated virus and its recombinant vectors

Gene Therapy volume 10, pages 964–976 (2003)Cite this article

Abstract

Recombinant adeno-associated virus (rAAV) vectors have emerged as highly promising for use in gene transfer for a variety of reasons, including lack of pathogenicity and wide host range. In addition, all virus-encoded genes have been removed from standard rAAV vectors, resulting in their comparatively low intrinsic immunogenicity. For gene replacement strategies, transgenes encoded by rAAV vectors may induce less robust host immune responses than other vectors in vivo. However, under appropriate conditions, host immune responses can be generated against rAAV-encoded transgenes, raising the potential for their use in vaccine development. In this review, we summarize current understanding of the generation of both undesirable and beneficial host immune responses directed against rAAV and encoded transgenes, and how they might be exploited for optimal use of this promising vector system.

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References

  1. Wong Jr KK, Chatterjee S . Adeno-associated virus based vectors as antivirals. Curr Top Microbiol Immunol 1996; 218: 145–170.

    CAS  PubMed  Google Scholar 

  2. Athanasopoulos T, Fabb S, Dickson G . Gene therapy vectors based on adeno-associated virus: characteristics and applications to acquired and inherited diseases. Int J Mol Med 2000; 6: 363–375.

    CAS  PubMed  Google Scholar 

  3. Carter BJ, Samulski RJ . Adeno-associated viral vectors as gene delivery vehicles. Int J Mol Med 2000; 6: 17–27.

    CAS  PubMed  Google Scholar 

  4. Zhao N, Liu DP, Liang CC . Hot topics in adeno-associated virus as a gene transfer vector. Mol Biotechnol 2001; 19: 229–237.

    CAS  PubMed  Google Scholar 

  5. Stilwell J, Samulski RJ . AAV has minimal effects on cellular gene expression compared to other viruses examined using high density microarrays [abstract]. Mol Ther 2001; 3: S131.

    Google Scholar 

  6. Brockstedt DG et al. Induction of immunity to antigens expressed by recombinant adeno-associated virus depends on the route of administration. Clin Immunol 1999; 92: 67–75.

    CAS  PubMed  Google Scholar 

  7. Manning WC et al. Genetic immunization with adeno-associated virus vectors expressing herpes simplex virus type 2 glycoproteins B and D. J Virol 1997; 71: 7960–7962.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Liu D et al. Recombinant adeno-associated virus expressing human papillomavirus type 16 E7 peptide DNA fused with heat shock protein DNA as a potential vaccine for cervical cancer. J Virol 2000; 74: 2888–2894.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Xin KQ et al. A novel recombinant adeno-associated virus vaccine induces a long-term humoral immune response to human immunodeficiency virus. Hum Gene Ther 2001; 12: 1047–1061.

    CAS  PubMed  Google Scholar 

  10. Chiriva-Internati M et al. Efficient generation of cytotoxic T lymphocytes against cervical cancer cells by adeno-associated virus/human papillomavirus type 16 E7 antigen gene transduction into dendritic cells. Eur J Immunol 2002; 32: 30–38.

    CAS  PubMed  Google Scholar 

  11. Liu Y et al. Rapid induction of cytotoxic T-cell response against cervical cancer cells by human papillomavirus type 16 E6 antigen gene delivery into human dendritic cells by an adenoassociated virus vector. Cancer Gene Ther 2001; 8: 948–957.

    CAS  PubMed  Google Scholar 

  12. Sun J et al. Immunogenicity of a p210BCR-ABL fusion domain candidate DNA vaccine targeted to dendritic cells by an rAAV vector in vitro. Cancer Res 2002; 62: 3175–3183.

    CAS  PubMed  Google Scholar 

  13. Sun J, Chatterjee S, Wong Jr KK . Immunogenic issues concerning recombinant adeno-associated virus vectors for gene therapy. Curr Gene Ther 2002; 2: 485–500.

    CAS  PubMed  Google Scholar 

  14. Berns KI, Giraud C . Biology of adeno-associated virus. Curr Top Microbiol Immunol 1996; 218: 1–23.

    CAS  PubMed  Google Scholar 

  15. Muzyczka N, Berns KI . (2001) In: Fields BN, Knipe DM, Howley, PM (eds.). Parvoviruses in Virology, 4th edn, Lippincott, Philadelphia, pp 2327–2360.

    Google Scholar 

  16. Meyers C et al. Ubiquitous human adeno-associated virus type 2 autonomously replicates in differentiating keratinocytes of a normal skin model. Virology 2002; 272: 338–346.

    Google Scholar 

  17. Kotin et al. Site-specific integration by adeno-associated virus. Proc Natl Acad Sci USA 1990; 87: 2211–2215.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Summerford C, Samulski RJ . Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type 2 virions. J Virol 1998; 72: 1438–1445.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Summerford C, Bartlett JS, Samulski RJ . AlphaVbeta5 integrin: a co-receptor for adeno-associated virus type 2 infection. Nat Med 1999; 5: 78–82.

    CAS  PubMed  Google Scholar 

  20. Qing K et al. Human fibroblast growth factor receptor 1 is a co-receptor for infection by adeno-associated virus 2. Nat Med 1999; 5: 71–77.

    CAS  PubMed  Google Scholar 

  21. Dong JY, Fan PD, Frizzell RA . Quantitative analysis of the packaging capacity of recombinant adeno-associated virus. Hum Gene Ther 1996; 7: 2101–2112.

    CAS  PubMed  Google Scholar 

  22. Clark KR, Liu X, McGrath JP, Johnson PR . Highly purified recombinant adeno-associated virus vectors are biologically active and free of detectable helper and wild-type viruses. Hum Gene Ther 1999; 10: 1031–1039.

    Article  CAS  PubMed  Google Scholar 

  23. Zolotukhin S et al. Recombinant adeno-associated virus purification using novel methods improves infectious titer and yield. Gene Therapy 1999; 6: 973–985.

    CAS  PubMed  Google Scholar 

  24. Chirmule N et al. Immune responses to adenovirus and adeno-associated virus in humans. Gene Therapy 1999; 6: 1574–1583.

    Article  CAS  PubMed  Google Scholar 

  25. 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 

  26. Chirmule N et al. Humoral immunity to adeno-associated virus type 2 vectors following administration to murine and nonhuman primate muscle. J Virol 2000; 74: 2420–2425.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Hernandez YJ et al. Latent adeno-associated virus infection elicits humoral but not cell-mediated immune responses in a nonhuman primate model. J Virol 1999; 73: 8549–8558.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Halbert CL, Standaert TA, Wilson CB, Miller AD . Successful readministration of adeno-associated virus vectors to the mouse lung requires transient immunosuppression during the initial exposure. J Virol 1998; 72: 9795–9805.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Manning et al. Transient immunosuppression allows transgene expression following readministration of adeno-associated viral vectors. Hum Gene Ther 1998; 9: 477–485.

    CAS  PubMed  Google Scholar 

  30. Xiao W et al. Route of administration determines induction of T-cell-independent humoral responses to adeno-associated virus vectors. Mol Ther 2000; 1: 323–329.

    CAS  PubMed  Google Scholar 

  31. Griffith TS et al. The immune response and the eye. TCR-alpha chain related molecules regulate the systemic immunity to antigen presented in the eye. Int Immunol 1995; 7: 1617–1625.

    CAS  PubMed  Google Scholar 

  32. Kezuka T, Streilein JW . In vitro generation of regulatory CD8+ T cells similar to those found in mice with anterior chamber-associated immune deviation. Invest Ophthalmol Vis Sci 2000; 41: 1803–1811.

    CAS  PubMed  Google Scholar 

  33. Anand V et al. A deviant immune response to viral proteins and transgene product is generated on subretinal administration of adenovirus and adeno-associated virus. Mol Ther 2002; 5: 125–132.

    CAS  PubMed  Google Scholar 

  34. Blacklow NR, Hoggan MD, Rowe WP . Serologic evidence for human infection with adenovirus-associated viruses. J Natl Cancer Inst 1968; 40: 319–327.

    CAS  PubMed  Google Scholar 

  35. Blacklow NR et al. A seroepidemiologic study of adenovirus-associated virus infection in infants and children. Am J Epidemiol 1971; 94: 359–366.

    CAS  PubMed  Google Scholar 

  36. Georg-Fries B, Biederlack S, Wolf J, zur Hausen H . Analysis of proteins, helper dependence, and seroepidemiology of a new human parvovirus. Virology 1984; 134: 64–71.

    CAS  PubMed  Google Scholar 

  37. Erles K, Sebokova P, Schlehofer JR . Update on the prevalence of serum antibodies (IgG and IgM) to adeno-associated virus (AAV). J Med Virol 1999; 59: 406–411.

    CAS  PubMed  Google Scholar 

  38. Hermanns J et al. Infection of primary cells by adeno-associated virus type 2 results in a modulation of cell cycle-regulating proteins. J Virol 1997; 71: 6020–6027.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Raj K, Ogston P, Beard P . Virus-mediated killing of cells that lack p53 activity. Nature 2001; 412: 914–917.

    CAS  PubMed  Google Scholar 

  40. Schlehofer JR . The tumor suppressive properties of adeno-associated viruses. Mutat Res 1994; 305: 303–313.

    CAS  PubMed  Google Scholar 

  41. Smith-Arica JR, Bartlett JS . Gene therapy: recombinant adeno-associated virus vectors. Curr Cardiol Rep 2001; 3: 43–49.

    CAS  PubMed  Google Scholar 

  42. Walz CM et al. Reduced prevalence of serum antibodies against adeno-associated virus type 2 in patients with adult T-cell leukaemia lymphoma. J Med Virol 2001; 65: 185–189.

    CAS  PubMed  Google Scholar 

  43. Xiao W et al. Gene therapy vectors based on adeno-associated virus type 1. J Virol 1999; 73: 3994–4003.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Moskalenko M et al. Epitope mapping of human anti-adeno-associated virus type 2 neutralizing antibodies: implications for gene therapy and virus structure. J Virol 2000; 74: 1761–1766.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Halbert CL et al. Repeat transduction in the mouse lung by using adeno-associated virus vectors with different serotypes. J Virol 2000; 74: 1524–1532.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Hildinger M et al. Hybrid vectors based on adeno-associated virus serotypes 2 and 5 for muscle-directed gene transfer. J Virol 2001; 75: 6199–6203.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Beck SE et al. Repeated delivery of adeno-associated virus vectors to the rabbit airway. J Virol 1999; 73: 9446–9455.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Anand V et al. Additional transduction events after subretinal readministration of recombinant adeno-associated virus. Hum Gene Ther 2000; 11: 449–57.

    CAS  PubMed  Google Scholar 

  49. Fisher KJ et al. Recombinant adeno-associated virus for muscle directed gene therapy. Nat Med 1997; 3: 306–312.

    Article  CAS  PubMed  Google Scholar 

  50. Kay MA et al. Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nat Genet 2000; 24: 257–261.

    CAS  PubMed  Google Scholar 

  51. Rutledge EA, Halbert CL, Russell DW . Infectious clones and vectors derived from adeno-associated virus (AAV) serotypes other than AAV type 2. J Virol 1998; 72: 309–319.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Gao GP et al. Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci USA 2002; 99: 11854–11859.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Tobiasch E et al. Discrimination between different types of human adeno-associated viruses in clinical samples by PCR. J Virol Methods 1998; 71: 17–25.

    CAS  PubMed  Google Scholar 

  54. Davidson BL et al. Recombinant adeno-associated virus type 2, 4, and 5 vectors: transduction of variant cell types and regions in the mammalian central nervous system. Proc Natl Acad Sci USA 2000; 97: 3428–3432.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Rabinowitz JE et al. Cross-packaging of a single adeno-associated virus (AAV) type 2 vector genome into multiple AAV serotypes enables transduction with broad specificity. J Virol 2002; 76: 791–801.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Chao H et al. Sustained and complete phenotype correction of hemophilia B mice following intramuscular injection of AAV1 serotype vector. Mol Ther 2001; 4: 217–222.

    CAS  PubMed  Google Scholar 

  57. Philip R et al. Efficient and sustained gene expression in primary T lymphocytes and primary and cultured tumor cells mediated by adeno-associated virus plasmid DNA complexed to cationic liposomes. Mol Cell Biol 1994; 14: 2411–2418.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Fan L et al. Efficient coexpression and secretion of anti-atherogenic human apolipoprotein AI and lecithin-cholesterol acyltransferase by cultured muscle cells using adeno-associated virus plasmid vectors. Gene Therapy 1998; 5: 1434–1440.

    CAS  PubMed  Google Scholar 

  59. Baudard M et al. Expression of the human multidrug resistance and glucocerebrosidase cDNAs from adeno-associated vectors: efficient promoter activity of AAV sequences and in vivo delivery via liposomes. Hum Gene Ther 1996; 7: 1309–1322.

    CAS  PubMed  Google Scholar 

  60. Tang X et al. Intravenous angiotensinogen antisense in AAV-based vector decreases hypertension. Am J Physiol 1999; 277: H2392–H2399.

    CAS  PubMed  Google Scholar 

  61. Podsakoff G, Wong Jr KK, Chatterjee S . Efficient gene transfer into nondividing cells by adeno-associated virus-based vectors. J Virol 1994; 68: 5656–5666.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Bradford GB, Williams B, Rossi R, Bertoncello I . Quiescence, cycling, and turnover in the primitive hematopoietic stem cell compartment. Exp Hematol 1997; 25: 445–453.

    CAS  PubMed  Google Scholar 

  63. Jetmore A et al. Homing efficiency, cell cycle kinetics, and survival of quiescent and cycling human CD34(+) cells transplanted into conditioned NOD/SCID recipients. Blood 2002; 99: 1585–1593.

    CAS  PubMed  Google Scholar 

  64. Fisher-Adams G et al. Integration of adeno-associated virus vectors in CD34+ human hematopoietic progenitor cells after transduction. Blood 1996; 88: 492–504.

    CAS  PubMed  Google Scholar 

  65. Ponnazhagan S et al. Adeno-associated virus type 2-mediated transduction in primary human bone marrow-derived CD34+ hematopoietic progenitor cells: donor variation and correlation of transgene expression with cellular differentiation. J Virol 1997; 71: 8262–8267.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Chatterjee S et al. Transduction of primitive human marrow and cord blood-derived hematopoietic progenitor cells with adeno-associated virus vectors. Blood 1999; 93: 1882–1894.

    CAS  PubMed  Google Scholar 

  67. Nathwani AC et al. Efficient gene transfer into human cord blood CD34+ cells and the CD34+CD38- subset using highly purified recombinant adeno-associated viral vector preparations that are free of helper virus and wild-type AAV. Gene Therapy 2000; 7: 183–195.

    CAS  PubMed  Google Scholar 

  68. Tan M et al. Adeno-associated virus 2-mediated transduction and erythroid lineage-restricted long-term expression of the human beta-globin gene in hematopoietic cells from homozygous beta-thalassemic mice. Mol Ther 2001; 3: 940–946.

    CAS  PubMed  Google Scholar 

  69. Shayakhmetov DM et al. A high-capacity, capsid-modified hybrid adenovirus/adeno-associated virus vector for stable transduction of human hematopoietic cells. J Virol 2002; 76: 1135–1143.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Girod A et al. Genetic capsid modifications allow efficient re-targeting of adeno-associated virus type 2. Nat Med 1999; 5: 1052–1056.

    CAS  PubMed  Google Scholar 

  71. Shi W, Arnold GS, Bartlett JS . Insertional mutagenesis of the adeno-associated virus type 2 (AAV2) capsid gene and generation of AAV2 vectors targeted to alternative cell-surface receptors. Hum Gene Ther 2001; 12: 1697–1711.

    CAS  PubMed  Google Scholar 

  72. Wobus CE et al. Monoclonal antibodies against the adeno-associated virus type 2 (AAV-2) capsid: epitope mapping and identification of capsid domains involved in AAV-2-cell interaction and neutralization of AAV-2 infection. J Virol 2000; 74: 9281–993.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Xie Q et al. The atomic structure of adeno-associated virus (AAV-2), a vector for human gene therapy. Proc Natl Acad Sci USA 2002; 99: 10405–10410.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Kay M et al. Transient immunomodulation with anti-CD40 ligand antibody and CTLA4Ig enhances persistence and secondary adenovirus-mediated gene transfer into mouse liver, Proc Natl Acad Sci USA 1997; 94: 4686–4691.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Fields PA et al. Risk and prevention of anti-factor IX formation in AAV-mediated gene transfer in the context of a large deletion of F9. Mol Ther 2001; 4: 201–210.

    CAS  PubMed  Google Scholar 

  76. Herzog RW et al. Stable gene transfer and expression of human blood coagulation factor IX after intramuscular injection of recombinant adeno-associated virus. Proc Natl Acad Sci USA 1997; 94: 5804–5809.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Herzog RW et al. Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector. Nat Med 1999; 5: 56–63.

    CAS  PubMed  Google Scholar 

  78. Snyder RO et al. Persistent and therapeutic concentrations of human factor IX in mice after hepatic gene transfer of recombinant AAV vectors. Nat Genet 1997; 16: 270–276.

    CAS  PubMed  Google Scholar 

  79. Snyder RO et al. Correction of hemophilia B in canine and murine models using recombinant adeno-associated viral vectors. Nat Med 1999; 5: 64–70.

    CAS  PubMed  Google Scholar 

  80. Wang L et al. 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.

    CAS  PubMed  Google Scholar 

  81. 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.

    CAS  PubMed  Google Scholar 

  82. Herzog RW et al. Muscle-directed gene transfer and transient immune suppression result in sustained partial correction of canine hemophilia B caused by a null mutation. Mol Ther 2001; 4: 192–200.

    CAS  PubMed  Google Scholar 

  83. Mount JD 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.

    CAS  PubMed  Google Scholar 

  84. Song S et al. Sustained secretion of human alpha-1-antitrypsin from murine muscle transduced with adeno-associated virus vectors. Proc Natl Acad Sci USA 1998; 95: 14384–14388.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Zaiss AK et al. Differential activation of innate immune responses by adenovirus and adeno-associated virus vectors. J Virol 2002; 76: 4580–4590.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Ponnazhagan S et al. Adeno-associated virus 2-mediated gene transfer in vivo: organ-tropism and expression of transduced sequences in mice. Gene 1997; 190: 203–210.

    CAS  PubMed  Google Scholar 

  87. Xiao X, Li J, Samulski RJ . Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J Virol 1996; 70: 8098–8108.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Fields PA 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.

    CAS  PubMed  Google Scholar 

  89. Sarukhan A et al. Successful interference with cellular immune responses to immunogenic proteins encoded by recombinant viral vectors. J Virol 2001; 75: 269–277.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Zhang Y, Chirmule N, Gao G, Wilson J . CD40 ligand-dependent activation of cytotoxic T lymphocytes by adeno-associated virus vectors in vivo: role of immature dendritic cells. J Virol 2000; 74: 8003–8010.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Sarukhan A, Soudais C, Danos O, Jooss K . Factors influencing cross-presentation of non-self antigens expressed from recombinant adeno-associated virus vectors. J Gene Med 2001; 3: 260–270.

    CAS  PubMed  Google Scholar 

  92. Riddell SR et al. T-cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients. Nat Med 1996; 2: 216–223.

    CAS  PubMed  Google Scholar 

  93. Song S et al. Stable therapeutic serum levels of human alpha-1 antitrypsin (AAT) after portal vein injection of recombinant adeno-associated virus (rAAV) vectors. Gene Therapy 2001; 8: 1299–1306.

    CAS  PubMed  Google Scholar 

  94. Jung SC et al. Adeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry mice. Proc Natl Acad Sci USA 2001; 98: 2676–2681.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. During MJ et al. An oral vaccine against NMDAR1 with efficacy in experimental stroke and epilepsy. Science 2000; 287: 1453–1460.

    CAS  PubMed  Google Scholar 

  96. Cordier L et al. Muscle-specific promoters may be necessary for adeno-associated virus-mediated gene transfer in the treatment of muscular dystrophies. Hum Gene Ther 2001; 12: 205–215.

    CAS  PubMed  Google Scholar 

  97. Yuasa K 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.

    CAS  PubMed  Google Scholar 

  98. Pastore L et al. Use of a liver-specific promoter reduces immune response to the transgene in adenoviral vectors. Hum Gene Ther 1999; 10: 1773–1781.

    CAS  PubMed  Google Scholar 

  99. Bronte V et al. Antigen expression by dendritic cells correlates with the therapeutic effectiveness of a model recombinant poxvirus tumor vaccine. Proc Natl Acad Sci USA 1997; 94: 3183–3188.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Nakai H et al. Adeno-associated viral vector-mediated gene transfer of human blood coagulation factor IX into mouse liver. Blood 1998; 91: 4600–4607.

    CAS  PubMed  Google Scholar 

  101. Nathwani AC et al. Factors influencing in vivo transduction by recombinant adeno-associated viral vectors expressing the human factor IX cDNA. Blood 2001; 97: 1258–1265.

    CAS  PubMed  Google Scholar 

  102. Xu L et al. CMV-beta-actin promoter directs higher expression from an adeno-associated viral vector in the liver than the cytomegalovirus or elongation factor 1 alpha promoter and results in therapeutic levels of human factor X in mice. Hum Gene Ther 2001; 12: 563–573.

    CAS  PubMed  Google Scholar 

  103. Fields PA et al. Intravenous administration of an E1/E3-deleted adenoviral vector induces tolerance to factor IX in C57BL/6 mice. Gene Therapy 2001; 8: 354–361.

    CAS  PubMed  Google Scholar 

  104. Chao H, Mao L, Bruce AT, Walsh CE . Sustained expression of human factor VIII in mice using a parvovirus-based vector. Blood 2000; 95: 1594–1599.

    CAS  PubMed  Google Scholar 

  105. Herzog RW et al. Influence of vector dose on factor IX-specific T and B cell responses in muscle-directed gene therapy. Hum Gene Ther 2002; 13: 1281–1291.

    CAS  PubMed  Google Scholar 

  106. Chao H, Walsh CE . Induction of tolerance to human factor VIII in mice. Blood 2001; 97: 3311–3312.

    CAS  PubMed  Google Scholar 

  107. Billings PR . In utero gene therapy: the case against. Nat Med 1999; 5: 255–256.

    CAS  PubMed  Google Scholar 

  108. Schneider H et al. Sustained delivery of therapeutic concentrations of human clotting factor IX – a comparison of adenoviral and AAV vectors administered in utero. J Gene Med 2002; 4: 46–53.

    PubMed  Google Scholar 

  109. Lipshutz GS et al. In utero delivery of adeno-associated viral vectors: intraperitoneal gene transfer produces long-term expression. Mol Ther 2001; 3: 284–292.

    CAS  PubMed  Google Scholar 

  110. Jerebtsova M, Batshaw ML, Ye X . Humoral immune response to recombinant adenovirus and adeno-associated virus after in utero administration of viral vectors in mice. Pediatr Res 2002; 52: 95–104.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Drs Stephen J Forman, David Senitzer, and the Hematology and Transfusion Services at the City of Hope for their continued support. This work was supported in part by Grants IR01CA75186, 5P01 CA30206, and CA33572 from the National Institutes of Health and National Cancer Institute.

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  1. Division of Hematology and Stem Cell Transplantation, CA, USA

    J Y Sun, V Anand-Jawa & K K Wong Jr

  2. Division of Virology, City of Hope, Duarte, CA, USA

    S Chatterjee & K K Wong Jr

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Sun, J., Anand-Jawa, V., Chatterjee, S. et al. Immune responses to adeno-associated virus and its recombinant vectors. Gene Ther 10, 964–976 (2003). https://doi.org/10.1038/sj.gt.3302039

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