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Immune responses to adenovirus and adeno-associated virus in humans

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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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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