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:

Progress and prospects: immune responses to viral vectors

Gene Therapy volume 17, pages 295–304 (2010)Cite this article

A Corrigendum to this article was published on 11 February 2010

Abstract

Viral vectors are potent gene delivery platforms used for the treatment of genetic and acquired diseases. However, just as viruses have evolved to infect cells efficiently, the immune system has evolved to fight off what it perceives as invading pathogens. Therefore, innate immunity and antigen-specific adaptive immune responses against vector-derived antigens reduce the efficacy and stability of in vivo gene transfer. In addition, a number of vectors are derived from parent viruses that humans encounter through natural infection, resulting in preexisting antibodies and possibly in memory responses against vector antigens. Similarly, antibody and T-cell responses may be directed against therapeutic gene products that often differ from the endogenous nonfunctional or absent protein that is being replaced. As details and mechanisms of such immune reactions are uncovered, novel strategies are being developed, and vectors are being specifically engineered to avoid, suppress or manipulate the response, ideally resulting in sustained expression and immune tolerance to the transgene product. This review provides a summary of our current knowledge of the interactions between the immune system adeno-associated virus, adenoviral and lentiviral vectors, and their transgene products.

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
Figure 2

Similar content being viewed by others

References

  1. Waters B, Lillicrap D . The immunology of gene transfer: an overview. In: Herzog RW (ed). Gene Therapy Immunology. Wiley-Balckwell: Hoboken, NJ, 2009, pp 1–18.

    Google Scholar 

  2. Zaiss AK, Muruve DA . Immunity to adeno-associated virus vectors in animals and humans: a continued challenge. Gene Therapy 2008; 15: 808–816.

    Article  CAS  PubMed  Google Scholar 

  3. McCaffrey AP, Fawcett P, Nakai H, McCaffrey RL, Ehrhardt A, Pham TT et al. The host response to adenovirus, helper-dependent adenovirus, and adeno-associated virus in mouse liver. Mol Ther 2008; 16: 931–941.

    Article  CAS  PubMed  Google Scholar 

  4. Zhu J, Huang X, Yang Y . The TLR9-MyD88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice. J Clin Invest 2009; 119: 2388–2398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zaiss AK, Cotter MJ, White LR, Clark SA, Wong NC, Holers VM et al. Complement is an essential component of the immune response to adeno-associated virus vectors. J Virol 2008; 82: 2727–2740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lin J, Calcedo R, Vandenberghe LH, Bell P, Somanathan S, Wilson JM . A new genetic vaccine platform based on an adeno-associated virus isolated from a rhesus macaque. J Virol 2009 (e-pub ahead of print 7 October 2009; doi:10.1128/JVI.01441-09).

  7. Calcedo R, Vandenberghe LH, Gao G, Lin J, Wilson JM . Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J Infect Dis 2009; 199: 381–390.

    Article  PubMed  Google Scholar 

  8. Mays LE, Vandenberghe LH, Xiao R, Bell P, Nam HJ, Agbandje-McKenna M et al. Adeno-associated virus capsid structure drives CD4-dependent CD8+ T cell response to vector encoded proteins. J Immunol 2009; 182: 6051–6060.

    Article  CAS  PubMed  Google Scholar 

  9. Murphy SL, Li H, Mingozzi F, Sabatino DE, Hui DJ, Edmonson SA et al. Diverse IgG subclass responses to adeno-associated virus infection and vector administration. J Med Virol 2009; 81: 65–74.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 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 

  11. Pien GC, Basner-Tschakarjan E, Hui DJ, Mentlik AN, Finn JD, Hasbrouck NC et al. Capsid antigen presentation flags human hepatocytes for destruction after transduction by adeno-associated viral vectors. J Clin Invest 2009; 119: 1688–1695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Li C, Hirsch M, Asokan A, Zeithaml B, Ma H, Kafri T et al. Adeno-associated virus type 2 (AAV2) capsid-specific cytotoxic T lymphocytes eliminate only vector-transduced cells coexpressing the AAV2 capsid in vivo. J Virol 2007; 81: 7540–7547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Li H, Murphy SL, Giles-Davis W, Edmonson S, Xiang Z, Li Y et al. Pre-existing AAV capsid-specific CD8+ T cells are unable to eliminate AAV-transduced hepatocytes. Mol Ther 2007; 15: 792–800.

    Article  CAS  PubMed  Google Scholar 

  14. Wang L, Figueredo J, Calcedo R, Lin J, Wilson JM . Cross-presentation of adeno-associated virus serotype 2 capsids activates cytotoxic T cells but does not render hepatocytes effective cytolytic targets. Hum Gene Ther 2007; 18: 185–194.

    Article  CAS  PubMed  Google Scholar 

  15. Siders W, Shields J, Kaplan J, Lukason M, Woodworth L, Wadsworth S et al. Cytotoxic T-lymphocyte (CTL) responses to the transgene product and not AAV capsid protein limit transgene expression in mice. Hum Gene Ther 2009; 20: 11–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Stieger K, Schroeder J, Provost N, Mendes-Madeira A, Belbellaa B, Meur GL et al. Detection of intact rAAV particles up to 6 years after successful gene transfer in the retina of dogs and primates. Mol Ther 2009; 17: 516–523.

    Article  CAS  PubMed  Google Scholar 

  17. Vandenberghe LH, Wilson JM . AAV as an immunogen. Curr Gene Ther 2007; 7: 325–333.

    Article  CAS  PubMed  Google Scholar 

  18. Zhong L, Li B, Jayandharan G, Mah CS, Govindasamy L, Agbandje-McKenna M et al. Tyrosine-phosphorylation of AAV2 vectors and its consequences on viral intracellular trafficking and transgene expression. Virology 2008; 381: 194–202.

    Article  CAS  PubMed  Google Scholar 

  19. Mingozzi F, Hasbrouck NC, Basner-Tschakarjan E, Edmonson SA, Hui DJ, Sabatino DE et al. Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver. Blood 2007; 110: 2334–2341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang Z, Kuhr CS, Allen JM, Blankinship M, Gregorevic P, Chamberlain JS et al. Sustained AAV-mediated dystrophin expression in a canine model of Duchenne muscular dystrophy with a brief course of immunosuppression. Mol Ther 2007; 15: 1160–1166.

    Article  CAS  PubMed  Google Scholar 

  21. Mingozzi F, Meulenberg JJ, Hui DJ, Basner-Tschakarjan E, Hasbrouck NC, Edmonson SA et al. AAV-1-mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells. Blood 2009; 114: 2077–2086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lowenstein PR, Mandel RJ, Xiong WD, Kroeger K, Castro MG . Immune responses to adenovirus and adeno-associated vectors used for gene therapy of brain diseases: the role of immunological synapses in understanding the cell biology of neuroimmune interactions. Curr Gene Ther 2007; 7: 347–360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Peden CS, Manfredsson FP, Reimsnider SK, Poirier AE, Burger C, Muzyczka N et al. Striatal readministration of rAAV vectors reveals an immune response against AAV2 capsids that can be circumvented. Mol Ther 2009; 17: 524–537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lin J, Zhi Y, Mays L, Wilson JM . Vaccines based on novel adeno-associated virus vectors elicit aberrant CD8+ T-cell responses in mice. J Virol 2007; 81: 11840–11849.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yuasa K, Yoshimura M, Urasawa N, Ohshima S, Howell JM, Nakamura A et al. Injection of a recombinant AAV serotype 2 into canine skeletal muscles evokes strong immune responses against transgene products. Gene Therapy 2007; 14: 1249–1260.

    Article  CAS  PubMed  Google Scholar 

  26. Lin SW, Hensley SE, Tatsis N, Lasaro MO, Ertl HC . Recombinant adeno-associated virus vectors induce functionally impaired transgene product-specific CD8+ T cells in mice. J Clin Invest 2007; 117: 3958–3970.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Velazquez VM, Bowen DG, Walker CM . Silencing of T lymphocytes by antigen-driven programmed death in recombinant adeno-associated virus vector-mediated gene therapy. Blood 2009; 113: 538–545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nayak S, Cao O, Hoffman BE, Cooper M, Zhou S, Atkinson MA et al. Prophylactic immune tolerance induced by changing the ratio of antigen-specific effector to regulatory T cells. J Thromb Haemost 2009; 7: 1523–1532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Martino AT, Nayak S, Hoffman BE, Cooper M, Liao G, Markusic DM et al. Tolerance induction to cytoplasmic beta-galactosidase by hepatic AAV gene transfer: implications for antigen presentation and immunotoxicity. PLoS One 2009; 4: e6376.

    Article  PubMed  PubMed Central  Google Scholar 

  30. 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 

  31. LoDuca PA, Hoffman BE, Herzog RW . Hepatic gene transfer as a means of tolerance induction to transgene products. Curr Gene Ther 2009; 9: 104–114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Breous E, Somanathan S, Vandenberghe LH, Wilson JM . Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver. Hepatology 2009; 50: 612–621.

    Article  CAS  PubMed  Google Scholar 

  33. Mingozzi F, Kleefstra A, Meulenberg J, Edmonson S, Morin D, Gaudet P et al. Modulation of T cell response to the AAV capsid in subjects undergoing intramuscular gene transfer for lipoprotein lipase deficiency. Hum Gene Ther 2008; 19: 1090.

    Google Scholar 

  34. Hoffman BE, Dobrzynski E, Wang L, Hirao L, Mingozzi F, Cao O et al. Muscle as a target for supplementary factor IX gene transfer. Hum Gene Ther 2007; 18: 603–613.

    Article  CAS  PubMed  Google Scholar 

  35. Passini MA, Bu J, Fidler JA, Ziegler RJ, Foley JW, Dodge JC et al. Combination brain and systemic injections of AAV provide maximal functional and survival benefits in the Niemann-Pick mouse. Proc Natl Acad Sci USA 2007; 104: 9505–9510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med 2008; 358: 2231–2239.

    Article  CAS  PubMed  Google Scholar 

  37. Cideciyan AV, Aleman TS, Boye SL, Schwartz SB, Kaushal S, Roman AJ et al. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci USA 2008; 105: 15112–15117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hauswirth W, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L et al. Phase I trial of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results. Hum Gene Ther 2008; 19: 979–990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Maguire AM, Simonelli F, Pierce EA, Pugh Jr EN, Mingozzi F, Bennicelli J et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med 2008; 358: 2240–2248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Li Q, Miller R, Han PY, Pang J, Dinculescu A, Chiodo V et al. Intraocular route of AAV2 vector administration defines humoral immune response and therapeutic potential. Mol Vis 2008; 14: 1760–1769.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Seiler MP, Cerullo V, Lee B . Immune response to helper dependent adenoviral mediated liver gene therapy: challenges and prospects. Curr Gene Ther 2007; 7: 297–305.

    Article  CAS  PubMed  Google Scholar 

  42. Yamaguchi T, Kawabata K, Koizumi N, Sakurai F, Nakashima K, Sakurai H et al. Role of MyD88 and TLR9 in the innate immune response elicited by serotype 5 adenoviral vectors. Hum Gene Ther 2007; 18: 753–762.

    Article  CAS  PubMed  Google Scholar 

  43. Huang X, Yang Y . Innate immune recognition of viruses and viral vectors. Hum Gene Ther 2009; 20: 203–301.

    Article  Google Scholar 

  44. Minari J, Mochizuki S, Sakurai K . Enhanced cytokine secretion owing to multiple CpG side chains of DNA duplex. Oligonucleotides 2008; 18: 337–344.

    Article  CAS  PubMed  Google Scholar 

  45. Appledorn DM, Patial S, McBride A, Godbehere S, Van Rooijen N, Parameswaran N et al. Adenovirus vector-induced innate inflammatory mediators, MAPK signaling, as well as adaptive immune responses are dependent upon both TLR2 and TLR9 in vivo. J Immunol 2008; 181: 2134–2144.

    Article  CAS  PubMed  Google Scholar 

  46. Zhu J, Huang X, Yang Y . A critical role for type I IFN-dependent NK cell activation in innate immune elimination of adenoviral vectors in vivo. Mol Ther 2008; 16: 1300–1307.

    Article  CAS  PubMed  Google Scholar 

  47. Nociari M, Ocheretina O, Schoggins JW, Falck-Pedersen E . Sensing infection by adenovirus: Toll-like receptor-independent viral DNA recognition signals activation of the interferon regulatory factor 3 master regulator. J Virol 2007; 81: 4145–4157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Muruve DA, Petrilli V, Zaiss AK, White LR, Clark SA, Ross PJ et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 2008; 452: 103–107.

    Article  CAS  PubMed  Google Scholar 

  49. Appledorn DM, McBride A, Seregin S, Scott JM, Schuldt N, Kiang A et al. Complex interactions with several arms of the complement system dictate innate and humoral immunity to adenoviral vectors. Gene Therapy 2008; 15: 1606–1617.

    Article  CAS  PubMed  Google Scholar 

  50. Othman M, Labelle A, Mazzetti I, Elbatarny HS, Lillicrap D . Adenovirus-induced thrombocytopenia: the role of von Willebrand factor and P-selectin in mediating accelerated platelet clearance. Blood 2007; 109: 2832–2839.

    CAS  PubMed  Google Scholar 

  51. Zhu J, Huang X, Yang Y . Type I IFN signaling on both B and CD4 T cells is required for protective antibody response to adenovirus. J Immunol 2007; 178: 3505–3510.

    Article  CAS  PubMed  Google Scholar 

  52. Peruzzi D, Dharmapuri S, Cirillo A, Bruni BE, Nicosia A, Cortese R et al. A novel chimpanzee serotype-based adenoviral vector as delivery tool for cancer vaccines. Vaccine 2009; 27: 1293–1300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. McCoy K, Tatsis N, Korioth-Schmitz B, Lasaro MO, Hensley SE, Lin SW et al. Effect of preexisting immunity to adenovirus human serotype 5 antigens on the immune responses of nonhuman primates to vaccine regimens based on human- or chimpanzee-derived adenovirus vectors. J Virol 2007; 81: 6594–6604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Mastrangeli A, Harvey BG, Yao J, Wolff G, Kovesdi I, Crystal RG et al. ‘Sero-switch’ adenovirus-mediated in vivo gene transfer: circumvention of anti-adenovirus humoral immune defenses against repeat adenovirus vector administration by changing the adenovirus serotype. Hum Gene Ther 1996; 7: 79–87.

    Article  CAS  PubMed  Google Scholar 

  55. O’Brien KL, Liu J, King SL, Sun YH, Schmitz JE, Lifton MA et al. Adenovirus-specific immunity after immunization with an Ad5 HIV-1 vaccine candidate in humans. Nat Med 2009; 15: 873–875.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Hutnick NA, Carnathan DG, Dubey SA, Cox KS, Kierstead L, Ratcliffe SJ et al. Baseline Ad5 serostatus does not predict Ad5 HIV vaccine-induced expansion of adenovirus-specific CD4+ T cells. Nat Med 2009; 15: 876–878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Brunetti-Pierri N, Stapleton GE, Palmer DJ, Zuo Y, Mane VP, Finegold MJ et al. Pseudo-hydrodynamic delivery of helper-dependent adenoviral vectors into non-human primates for liver-directed gene therapy. Mol Ther 2007; 15: 732–740.

    Article  CAS  PubMed  Google Scholar 

  58. Seregin SS, Appledorn DM, McBride AJ, Schuldt NJ, Aldhamen YA, Voss T et al. Transient pretreatment with glucocorticoid ablates innate toxicity of systemically delivered adenoviral vectors without reducing efficacy. Mol Ther 2009; 17: 685–696.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sack BK, Herzog RW . Evading the immune response upon in vivo gene therapy with viral vectors. Curr Opin Mol Ther 2009; 11: 493–503.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Follenzi A, Santambrogio L, Annoni A . Immune responses to lentiviral vectors. Curr Gene Ther 2007; 7: 306–315.

    Article  CAS  PubMed  Google Scholar 

  61. Limberis MP, Bell CL, Heath J, Wilson JM . Activation of Transgene-specific T Cells Following Lentivirus-mediated Gene Delivery to Mouse Lung. Mol Ther 2009 (e-pub ahead of print 1 September 2009; doi:10.1038/mt.2009.190).

  62. Sinn PL, Burnight ER, Hickey MA, Blissard GW, McCray PB Jr . Persistent gene expression in mouse nasal epithelia following feline immunodeficiency virus-based vector gene transfer. J Virol 2005; 79: 12818–12827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kremer KL, Dunning KR, Parsons DW, Anson DS . Gene delivery to airway epithelial cells in vivo: a direct comparison of apical and basolateral transduction strategies using pseudotyped lentivirus vectors. J Gene Med 2007; 9: 362–368.

    Article  CAS  PubMed  Google Scholar 

  64. Brown BD, Sitia G, Annoni A, Hauben E, Sergi LS, Zingale A et al. In vivo administration of lentiviral vectors triggers a type I interferon response that restricts hepatocyte gene transfer and promotes vector clearance. Blood 2007; 109: 2797–2805.

    Article  CAS  PubMed  Google Scholar 

  65. Markusic DM, van Til NP, Hiralall JK, Oude Elferink RP, Seppen J . Reduction of liver macrophage transduction by pseudotyping lentiviral vectors with a fusion envelope from Autographa californica GP64 and Sendai virus F2 domain. BMC Biotechnol 2009; 9: 85.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Pichlmair A, Diebold SS, Gschmeissner S, Takeuchi Y, Ikeda Y, Collins MK et al. Tubulovesicular structures within vesicular stomatitis virus G protein-pseudotyped lentiviral vector preparations carry DNA and stimulate antiviral responses via Toll-like receptor 9. J Virol 2007; 81: 539–547.

    Article  CAS  PubMed  Google Scholar 

  67. Brown BD, Cantore A, Annoni A, Sergi LS, Lombardo A, Della Valle P et al. A microRNA-regulated lentiviral vector mediates stable correction of hemophilia B mice. Blood 2007; 110: 4144–4152.

    Article  CAS  PubMed  Google Scholar 

  68. Annoni A, Brown BD, Cantore L, Sergi Sergi L, Naldini L, Roncarolo MG . In vivo delivery of a microRNA regulated transgene induces antigen-specific regulatory T cells and promotes immunological tolerance. Blood 2009 (e-pub ahead of print 30 September 2009; doi:10.1182/blood-2009-04-214569).

  69. Brantly ML, Chulay JD, Wang L, Mueller C, Humphries M, Spencer LT et al. Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy. Proc Natl Acad Sci USA 2009; 106: 16363–16368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lasaro MO, Ertl HC . New insights on adenovirus as vaccine vectors. Mol Ther 2009; 17: 1333–1339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department Pediatrics, University of Florida, Gainesville, FL, USA

    S Nayak & R W Herzog

Authors
  1. S Nayak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R W Herzog
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R W Herzog.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nayak, S., Herzog, R. Progress and prospects: immune responses to viral vectors. Gene Ther 17, 295–304 (2010). https://doi.org/10.1038/gt.2009.148

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2009.148

Keywords

This article is cited by

Search

Advanced search

Quick links