Abstract
Vectors based on human adenovirus (Ad) and adeno-associated virus (AAV) are being evaluated for human gene therapy. The response of the host to the vector, in terms of antigen-specific immunity, will play a substantial role in clinical outcome. We have surveyed cohorts of normal subjects and cystic fibrosis patients for pre-existing immunity to these viruses, caused by naturally acquired infections. A number of humoral and cellular assays to adenovirus serotype 5 (Ad5) and adeno-associated virus serotype 2 (AAV2) were performed from serum and peripheral blood mononuclear cells. Virtually all subjects had Ig to Ad5 although only 55% of these antibodies neutralized virus (NAB). Approximately two of three patients demonstrated CD4+ T cells that proliferated to Ad antigens of which most were of the TH1 subset, based on cytokine secretion. A substantially different pattern of immune responses was observed to AAV2. Although virtually all patients had Ig to AAV2, most of these antibodies were not neutralizing (32% NAB) and only 5% of patients had peripheral blood lymphocytes that proliferated in response to AAV2 antigens. These studies demonstrate marked heterogeneity in pre-existing immunity to Ad5 and AAV2 in human populations. The impact of these findings on outcome following gene therapy will require further study.
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References
Wilson J . Gene therapy for cystic fibrosis: challenges and future directions J Clin Invest 1995 96: 2547–2554
Wilson JM . Adenoviruses as gene-delivery vehicles New Engl J Med 1996 334: 1185–1187
Crystal R . Transfer of genes to humans: early lessons and obstacles to success Science 1995 270: 404–410
Flotte TR, Carter BJ . Adeno-associated virus vectors for gene therapy Gene Therapy 1995 2: 357–362
Koeberl DD et al. Persistent expression of human clotting factor IX from mouse liver after intravenous injection of adeno-associated virus vectors Proc Natl Acad Sci USA 1997 94: 1426–1431
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
Schmitz H, Wigand R, Henrich W . Worldwide epidemiology of human adenovirus infections Am J Epidemiol 1983 117: 455–466
Crystal RG et al. Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis Nat Genet 1994 8: 42–51
Knowles M et al. A double-blind vehicle controlled study of adenoviral vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis New Engl J Med 1995 333: 823–831
Rosenfeld MA et al. In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium Cell 1992 68: 143–155
Gahery-Segard H et al. Phase I trial of recombinant adenovirus gene transfer in lung cancer: longitudinal study of the immune responses to transgene and viral products J Clin Invest 1997 100: 2218–2226
Wold SM, Tollefson AE, Hermiston TW . Strategies of immune modulation by adenoviruses In: G McFadden (ed) Viroceptors, Virokines and Related Immune Modulators Encoded by DAN Viruses RG Landes 1994 pp 147–185
Takafuji ET, Gaydos JC, Allen RG, Top FH . Simultaneous administration of live, enteric coated adenovirus 4, 7 and 21 vaccines: safety and immunogenecity J Infect Dis 1979 140: 48–53
Atchinson R . Adenovirus-associated defective virus particles Science 1965 149: 754–756
McKeon C, Ramulski RJ . NIDDK workshop on AAV vectors: gene transfer into quiescent cells Hum Gene Ther 1996 7: 1615–1619
Kotin RM . Prospects for the use of adeno-associated virus as a vector for human gene therapy Hum Gene Ther 1994 5: 793–801
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
Fisher KJ et al. Recombinant adeno-associated virus for muscle directed gene therapy Nature Med 1997 3: 306–312
Jooss K, Yang Y, Fisher KJ, Wilson JM . Transduction of dendritic cells by DNA viral vectors directs the immune responses to transgene products in muscle fibers J Virol 1998 72: 4212–4223
Yang Y, Greenough K, Wilson JM . Transient immune blockade prevents formation of neutralizing antibody to recombinant adenovirus and allows repeated transfer to mouse liver Gene Therapy 1996 3: 412–420
Guibinga G-H et al. Combinatorial blockade of calcineurin and CD28 signaling facilitates primary and secondary therapeutic gene transfer by adenovirus vectors in dystrophic (mdx) mouse muscles J Virol 1998 72: 4601–4609
Zhang H-G et al. Application of a fas ligand encoding a recombinant adenovirus vector for prolongation of transgene expression J Virol 1998 72: 2483–2490
Ilan Y et al. Insertion of the adenoviral E3 region into a recombinant viral vector prevents antiviral humoral and cellular immune responses and permits long-term gene expression Proc Natl Acad Sci USA 1997 94: 2587–2592
Flomenberg P, Piaskowski V, Truitt RL, Casper JT . Characterization of human proliferative T cell response to adenovirus J Infect Dis 1995 171: 1090–1096
Smith CA, Woodruff LS, Kitchingman GR, Rooney CM . Adenovirus-pulsed dendritic cells stimulate human virus-specific T-cell responses in vitro J Virol 1996 70: 6733–6740
Abbas AK, Murphy KM, Sher A . Functional diversity of helper T lymphocytes Nature 1996 383: 787–793
Ma Y et al. Inhibition of collagen-induced arthritis in mice by viral IL-10 gene transfer J Immunol 1998 161: 1516–1524
Fukaura H et al. Induction of circulating myelin basic protein and proteolipid protein-specificc transforming growth factor-β-1 secreting Th3 T cells by oral administration of myelin inmultiple sclerosis patients J Clin Invest 1996 98: 70–77
Pohl-Koppe A et al. Identification of a T cell subset capable of both IFN-γ and IL-10 secretion in patients with chronic Borrelia burgdorferi infection J Immunol 1998 160: 1804–1810
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 trila for localized mesothelioma Hum Gene Ther 1998 9: 2121–2133
Acknowledgements
The cooperation of the human subjects involved in this study was greatly appreciated. We thank the Vector and Immunology Cores of the Institute for Human Gene Therapy for their help, and Biogen for providing the 5C8 antibody. This work was supported by the CF Foundation and NIH (P50DK49136 and P30DK47757) and Genovo, Inc, a biotechnology company, which Dr J Wilson founded and in which he holds equity.
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Chirmule, N., Propert, K., Magosin, S. et al. Immune responses to adenovirus and adeno-associated virus in humans. Gene Ther 6, 1574–1583 (1999). https://doi.org/10.1038/sj.gt.3300994
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DOI: https://doi.org/10.1038/sj.gt.3300994
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