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Research Article Free access | 10.1172/JCI33138

Recombinant adeno-associated virus vectors induce functionally impaired transgene product–specific CD8+ T cells in mice

Shih-Wen Lin,1,2 Scott E. Hensley,1,2 Nia Tatsis,2 Marcio O. Lasaro,2 and Hildegund C.J. Ertl2

1University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. 2The Wistar Institute, Philadelphia, Pennsylvania, USA.

Address correspondence to: Hildegund C.J. Ertl, The Wistar Institute, 3601 Spruce St., Philadelphia, Pennsylvania 19104, USA. Phone: (215) 898-3855; Fax: (215) 573-2097; E-mail: ertl@wistar.upenn.edu.

Find articles by Lin, S. in: PubMed | Google Scholar

1University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. 2The Wistar Institute, Philadelphia, Pennsylvania, USA.

Address correspondence to: Hildegund C.J. Ertl, The Wistar Institute, 3601 Spruce St., Philadelphia, Pennsylvania 19104, USA. Phone: (215) 898-3855; Fax: (215) 573-2097; E-mail: ertl@wistar.upenn.edu.

Find articles by Hensley, S. in: PubMed | Google Scholar

1University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. 2The Wistar Institute, Philadelphia, Pennsylvania, USA.

Address correspondence to: Hildegund C.J. Ertl, The Wistar Institute, 3601 Spruce St., Philadelphia, Pennsylvania 19104, USA. Phone: (215) 898-3855; Fax: (215) 573-2097; E-mail: ertl@wistar.upenn.edu.

Find articles by Tatsis, N. in: PubMed | Google Scholar

1University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. 2The Wistar Institute, Philadelphia, Pennsylvania, USA.

Address correspondence to: Hildegund C.J. Ertl, The Wistar Institute, 3601 Spruce St., Philadelphia, Pennsylvania 19104, USA. Phone: (215) 898-3855; Fax: (215) 573-2097; E-mail: ertl@wistar.upenn.edu.

Find articles by Lasaro, M. in: PubMed | Google Scholar

1University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. 2The Wistar Institute, Philadelphia, Pennsylvania, USA.

Address correspondence to: Hildegund C.J. Ertl, The Wistar Institute, 3601 Spruce St., Philadelphia, Pennsylvania 19104, USA. Phone: (215) 898-3855; Fax: (215) 573-2097; E-mail: ertl@wistar.upenn.edu.

Find articles by Ertl, H. in: PubMed | Google Scholar

Published November 15, 2007 - More info

J Clin Invest. https://doi.org/10.1172/JCI33138.
© 2007 The American Society for Clinical Investigation
Published November 15, 2007 - Version history
Received: June 29, 2007; Accepted: September 24, 2007
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Abstract

Recombinant adeno-associated virus (rAAV) vectors were used in human trials as carriers of vaccines for HIV-1 after encouraging preclinical results. However, the clinical trials yielded disappointing results. Here we demonstrated that in mice, rAAV vectors expressing the gene encoding HIV-1 gag stimulated gag-specific CD8+ T cells, but these T cells failed to expand after a booster immunization with a replication-defective adenoviral (Ad) vector also expressing gag. We tested rAAV vectors of different serotypes expressing HIV-1 gag for induction of transgene product–specific CD8+ T cells and found that the immunoinhibitory effect of rAAV priming observed with different AAV serotypes was transgene product specific, was independent of the interval between prime and boost, and extended to boosts with vaccine modalities other than Ad vectors. rAAV vector–induced CD8+ T cells proliferated poorly, produced low levels of IFN-γ in response to gag stimulation, and upregulated immunoinhibitory molecules. These T cells did not protect efficiently against challenge with a surrogate pathogen. Finally, we showed that the impaired proliferative capacity of the T cells was caused by persistence of the antigen-encoding rAAV vectors and could be reversed by placing the CD8+ T cells in an antigen-free environment. Our data suggest that rAAV vectors induce functionally impaired T cells and could dampen the immune response to a natural infection.

Version history
  • Version 1 (November 15, 2007): No description
  • Version 2 (November 15, 2007): No description
  • Version 3 (December 3, 2007): No description
  • Version 4 (December 3, 2007): No description
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