Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Immunity to adenovirus and adeno-associated viral vectors: implications for gene therapy

Gene Therapy volume 10, pages 955–963 (2003)Cite this article

Abstract

Viral vectors have provided effective methods for in vivo gene delivery for therapeutic purposes. The ability of viruses to infect a wide variety of cell types in vivo has been exploited for several applications, such as liver, lung, muscle, brain, eye and many others. Immune responses directed towards the viral capsids and the transgene products have severely affected the ability of these vectors to induce long-term gene expression. This paper reviews the influence of viral vectors on antigen-presenting cells (APC), which are central to the induction of innate as well as adaptive immune responses. In this respect, we have focused on adenovirus and adeno-associated viruses because of the polar responses these vector systems induce in vivo. While adenovirus vector can induce significant inflammatory responses, adeno-associated viral vectors are characterized by their inability to consistantly induce immune responses to the transgene product. Understanding the mechanism of infection, transduction and activation of APC by viral vectors will provide strategies to develop safe vectors and prevent immune responses in gene therapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Zoon K . www.fda.go 2000.

  2. Somia N, Verma IM . Gene therapy: trial and tribunals. Nat Rev 2000; 1: 91–99.

    Article  CAS  Google Scholar 

  3. Bromberg JS, Debruyne LA, Qin L . Interactions between the immune system and gene therapy vectors: bidirectional regulation of response and expression. Adv Immunol 1998; 69: 353–409.

    Article  CAS  PubMed  Google Scholar 

  4. Hackett NR, Kaminsky SM, Sonmdhi D, Crystal RG . Anticector and antitransgene host responses in gene therapy. Curr Opin Mol Ther 2000; 2: 376–382.

    CAS  PubMed  Google Scholar 

  5. Yang Y et al. Cellular immunity fo viral antigens limits E1-deleted adenoviruses for gene therapy. Proc Natl Acad Sci USA 1994; 91: 4407–4411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tripathy SK BH, Goldwasser E, Leiden JM . Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors. Nat Med 1996; 2: 545–550.

    Article  CAS  PubMed  Google Scholar 

  7. Banchereau J, Steinman RM . Dendritic cells and the control of immunity. Nature 1998; 392: 245–252.

    Article  CAS  PubMed  Google Scholar 

  8. Janeway CA, Medzhitov R . The role of innate immunity in the adpative immune response. Sem Immunol 1998; 10: 349–350.

    Article  Google Scholar 

  9. Gallucci S, Matzinger P . Danger signals: SOS to the immune system. Curr Opin Immunol 2001; 13: 114–119.

    Article  CAS  PubMed  Google Scholar 

  10. Akira S, Takeda K, Kaisho T . Toll-like ceptros: critical proteins linking innate and acquired immunity. Nat Immunol 2001; 2: 675–680.

    Article  CAS  PubMed  Google Scholar 

  11. Sallusto F, Lanzavecchia A . Understanding dendritic cell and T-lymphocyte traffic through the analysis of chemokine receptor expression. Immunol Rev 2000; 177: 134–140.

    Article  CAS  PubMed  Google Scholar 

  12. Bluestone JA . New perspectives of CD28-B7-mediated T cell costimulation. Immunity 1995; 2: 555–559.

    Article  CAS  PubMed  Google Scholar 

  13. Schmitz H, Wigand R, Heinrich W . Worldwide epidemiology of human adenovirus infections. Am J Epidemiol 1983; 117: 455–466.

    Article  CAS  PubMed  Google Scholar 

  14. Wold SM, Tollefson AE, Hermiston TW . Strategies of immune modulation by adenoviruses. In: McFadden G (ed). Viroceptors, Virokines and Related Immune Modulators Encoded by DNA Viruses. R.G. Landes Company: 1994, pp 147–185.

    Google Scholar 

  15. 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 

  16. Mack CA et al. Circumvention of anti-adenovirus neutralizing immunity by administration of an adenoviral vector of an alternate serotype. Hum Gene Ther 1997; 8: 99–109.

    Article  CAS  PubMed  Google Scholar 

  17. Zabner J et al. A chimeric type 2 adenovirus vector with a type 17 fiber enhances gene transfer to human airway epithelia. J Virol 1999; 73: 8689–8695.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Farina SF et al. Replication-defective vector based on a chimpanzee adenovirus. J Virol 2001; 75: 11603–11613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Klonjkowski B et al. A recombinant E1-deleted canine adenoviral vector capable of transduction and expression of a transgene in human-derived cells and in vivo. Hum Gene Ther 1997; 8: 2103–2115.

    Article  CAS  PubMed  Google Scholar 

  20. Chen HH et al. Persistence in muscle of an adenoviral vector that lacks all viral genes. Proc Natl Acad Sci 1997; 94: 1645–1650.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Morsy MA et al. An adenoviral vector deleted of all viral coding sequences results in enhanced safety and extended expression of a leptin transgene. Proc Natl Acad Sci USA 1998; 95: 7866–7871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Morral N et al. Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons. Proc Natl Acad Sci USA 1999; 96: 12816–12821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rodriguez R et al. Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells. Cancer Res 1997; 57: 2559–2563.

    CAS  PubMed  Google Scholar 

  24. Bischoff JR et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996; 274: 373–376.

    Article  CAS  PubMed  Google Scholar 

  25. Kirn DH, Martuza RL, Zwibel J . Replication-selective virotherapy for cancer: biological principles, risk management and future directions. Nat Med 2001; 7: 781–787.

    Article  CAS  PubMed  Google Scholar 

  26. Breyer B et al. Adenoviral vector mediated gene transfer in human gene therapy. Curr Gene Ther 2001; 1: 149–162.

    Article  CAS  PubMed  Google Scholar 

  27. Kay MA, Glorioso JC, Naldini L . Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics. Nat Med 2001; 7: 33–40.

    Article  CAS  PubMed  Google Scholar 

  28. Monahan PE, Samulski RJ . Adeno-associated virus vectors for gene therapy: more pros than cons? Mol Med Today 2000; 6: 433–440.

    Article  CAS  PubMed  Google Scholar 

  29. Dutheil N, Shi F, Dupressoir T, Linden RM . Adeno-associated virus site-specifically integrates into a muscle-specific DNA region. Proc Natl Acad Sci USA 2000; 97: 4862–4866.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Young Jr SM, Samulski RJ . Adeno-associated virus (AAV) site-specific recombination does not require a Rep-dependent origin of replication within the AAV terminal repeat. Proc Natl Acad Sci USA 2001; 98: 13525–13530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rabinowitz JE, Samulski RJ . Building a better vector: the manipulation of AAV virions. Virology 2000; 278: 301–308.

    Article  CAS  PubMed  Google Scholar 

  32. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Xiao X, Li J, McCown TJ, Samulski RJ . Gene transfer by adeno-associated virus vectors into the central nervous system. Exp Neurol 1997; 144: 113–124.

    Article  CAS  PubMed  Google Scholar 

  34. 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 

  35. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  37. Kessler PD 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 

  38. 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.

    Article  CAS  PubMed  Google Scholar 

  39. Ferrari FK, Samulski T, Shenk T, Samulski RJ . Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors. J Virol 1996; 70: 3227–3234.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Malik AK et al. Kinetics of recombinant adeno-associated virus-mediated gene transfer. J Virol 2000; 74: 3555–3565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Raper SE et al. A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency. Hum Gene Ther 2002; 1: 163–175.

    Article  Google Scholar 

  42. Mickelson CA . Recombinant DNA Advisory Committee. Hum Gene Ther 2000; 11: 1591–1621.

    Article  Google Scholar 

  43. Crystal RG et al. Analysis of risk factors for local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of comorbid conditions. Hum Gene Ther 2002; 13: 65–100.

    Article  CAS  PubMed  Google Scholar 

  44. Harvey BG et al. Safety of local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of morbid conditions. Hum Gene Ther 2002; 13: 15–63.

    Article  CAS  PubMed  Google Scholar 

  45. Ben-Gary H et al. Systemic interleukin-6 responses following administration of adenovirus gene transfer vectors to humans by different routes. Mol Ther 2002; 6: 287–297.

    Article  PubMed  Google Scholar 

  46. Reid T et al. Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: a phase I trial. Gene Therapy 2001; 8: 1618–1626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Brusilow SW, Maestri NE . Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr 1996; 43: 127–170.

    CAS  PubMed  Google Scholar 

  48. Lozier JN et al. Toxicity of a first-generation adenoviral vector in rhesus macaques. Hum Gene Ther 2002; 13: 113–124.

    Article  CAS  PubMed  Google Scholar 

  49. Zhang Y, Chirmule N, Wilson JM . Acute cytokine responses to systemic adenovirus vector is mediated by dendritic cells and macrophages. Mol Ther 2001; 3: 697–707.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Varnavski AN et al. Preexisting immunity to adenovirus in rhesus monkeys fails to prevent vector-induced toxicity. J Virol 2002; 76: 5711–5719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kafri T et al. Cellular immune response to adenoviral vector infected cells does not require de novo viral gene expression: implications for gene therapy. Proc Natl Acad Sci USA 1998; 95: 11377–11382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Croyle MA, Chirmule N, Zhang Y, Wilson JM . “Stealth” adenoviruses blunt cell-mediated and humoral immune responses against the virus and allow for significant gene expression upon readministration in the lung. J Virol 2001; 75: 4792–4801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. O'Riordan CR et al. PEGylation of adenovirus with retention of infectivity and protection from neutralizing antibody in vitro and in vivo. Hum Gene Ther 1999; 10: 1349–1358.

    Article  CAS  PubMed  Google Scholar 

  55. Croyle MA, Chirmule N, Zhang Y, Wilson JM . PEGylation of E1-deleted adenovirus vectors allows significant gene expression on readministration to liver. Hum Gene Ther 2002; 13: 1887–1900.

    Article  CAS  PubMed  Google Scholar 

  56. 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 

  57. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 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.

    Article  CAS  PubMed  Google Scholar 

  59. Ponnazhagan S, Mahendra G, Curiel DT, Shaw DR . Adeno-associated virus type 2-mediated transduction of human monocyte-derived dendritic cells: implications for ex vivo immunotherapy. J Virol 2001; 75: 9493–9501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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 

  61. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Prasad SA et al. Recombinant adenoviruses induce CD8 T cell responses to an inserted protein whose expression is limited to nonimmune cells. J Immunol 2001; 166: 4809–4812.

    Article  CAS  PubMed  Google Scholar 

  65. Kurts C et al. Major histocompatibility complex class I-restricted cross-presentation is biased towards high dose antigens and those released during cellular destruction. J Exp Med 1998; 188: 409–414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Snyder RO et al. Efficient and stable adeno-associated virus-mediated transduction in the skeletal muscle of adult immunocompetent mice. Hum Gene Ther 1997; 8: 1891–1900.

    Article  CAS  PubMed  Google Scholar 

  67. Camargo FD et al. Germline incorporation of a replication-defective adenoviral vector in mice does not alter immune responses to adenoviral vectors. Mol Ther 2000; 2: 496–504.

    Article  CAS  PubMed  Google Scholar 

  68. DeMatteo RP et al. Long-lasting adenovirus transgene expression in mice through neonatal intrathymic tolerance induction without the use of immunosuppression. J Virol 1997; 71: 5330–5335.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 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.

    Article  PubMed  Google Scholar 

  70. 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 

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

    Article  CAS  PubMed  Google Scholar 

  72. Molnar-Kimber KL et al. Impact of pre-existing and induced humoral and cellular immune responses in an adenovirus-based gene therapy phase I clinical trial for localized mesothelioma. Hum Gene Ther 1998; 9: 2121–2133.

    Article  CAS  PubMed  Google Scholar 

  73. Anand V et al. Additional transduction events after subretinal readministration of recombinant adeno-associated virus. Hum Gene Ther 2000; 11: 449–457.

    Article  CAS  PubMed  Google Scholar 

  74. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 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.

    Article  CAS  PubMed  Google Scholar 

  76. Yang Y et al. Transient subversion of CD40 ligand function diminishes immune responses to adenovirus vectors in mouse liver and lung tissues. J Virol 1996; 70: 6370–6377.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Chen Y, Yu DC, Charlton D, Henderson DR . Pre-existent adenovirus antibody inhibits systemic toxicity and antitumor activity of CN706 in the nude mouse LNCaP xenograft model: implications and proposals for human therapy. Hum Gene Ther 2000; 11: 1553–1567.

    Article  CAS  PubMed  Google Scholar 

  78. Rahman A et al. Specific depletion of human anti-adenovirus antibodies facilitates transduction in an in vivo model for systemic gene therapy. Mol Ther 2001; 3: 768–778.

    Article  CAS  PubMed  Google Scholar 

  79. Kremer EJ, Boutin S, Chillon M, Danos O . Canine adenovirus vectors: an alternative for adenovirus-mediated gene transfer. J Virol 2000; 74: 505–512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Jooss K, Turka LA, Wilson JM . Blunting of immune responses to adenoviral vectors in mouse liver and lung with CTLA4Ig. Gene Ther 1998; 5: 309–319.

    Article  CAS  PubMed  Google Scholar 

  81. Kay MA 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cell Genesys, South San Francisco, CA, USA

    K Jooss

  2. Merck and Co. Inc., West Point, PA, USA

    N Chirmule

Authors
  1. K Jooss
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N Chirmule
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jooss, K., Chirmule, N. Immunity to adenovirus and adeno-associated viral vectors: implications for gene therapy. Gene Ther 10, 955–963 (2003). https://doi.org/10.1038/sj.gt.3302037

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302037

This article is cited by

Search

Advanced search

Quick links