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Journal of Virology, July 2007, p. 7540-7547, Vol. 81, No. 14
0022-538X/07/$08.00+0     doi:10.1128/JVI.00529-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Adeno-Associated Virus Type 2 (AAV2) Capsid-Specific Cytotoxic T Lymphocytes Eliminate Only Vector-Transduced Cells Coexpressing the AAV2 Capsid In Vivo{triangledown}

Chengwen Li,1 Matthew Hirsch,1 Aravind Asokan,1 Brian Zeithaml,1 Hong Ma,1 Tal Kafri,1,3 and R. Jude Samulski1,2*

Gene Therapy Center,1 Department of Pharmacology,2 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 275993

Received 13 March 2007/ Accepted 23 April 2007

A recent clinical trial has suggested that recombinant adeno-associated virus (rAAV) vector transduction in humans induces a cytotoxic T-lymphocyte (CTL) response against the AAV2 capsid. To directly address the ability of AAV capsid-specific CTLs to eliminate rAAV-transduced cells in vitro and in vivo in mice, we first demonstrated that AAV2 capsid-specific CTLs could be induced by dendritic cells with endogenous AAV2 capsid expression or pulsed with AAV2 vectors. These CTLs were able to kill a cell line stable for capsid expression in vitro and also in a mouse tumor xenograft model in vivo. Parent colon carcinoma (CT26) cells transduced with a large amount of AAV2 vectors in vitro were also destroyed by these CTLs. To determine the effect of CTLs on the elimination of target cells transduced by AAV2 vectors in vivo, we carried out adoptive transfer experiments. CTLs eliminated liver cells with endogenous AAV2 capsid expression but not liver cells transduced by AAV2 vectors, regardless of the reporter genes. Similar results were obtained for rAAV2 transduction in muscle. Our data strongly suggest that AAV vector-transduced cells are rarely eliminated by AAV2 capsid-specific CTLs in vivo, even though the AAV capsid can induce a CTL response. In conclusion, AAV capsid-specific CTLs do not appear to play a role in elimination of rAAV-transduced cells in a mouse model. In addition, our data suggest that the mouse model may not mimic the immune response noted in humans and additional modification to AAV vectors may be required for further study in order to elicit a similar cellular immune response.

* Corresponding author. Mailing address: Gene Therapy Center, 7119 Thurston-Bowles, CB 7352, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. Phone: (919) 962-3285. Fax: (919) 966-0907. E-mail: RJS{at}med.unc.edu

{triangledown} Published ahead of print on 2 May 2007.

Journal of Virology, July 2007, p. 7540-7547, Vol. 81, No. 14
0022-538X/07/$08.00+0     doi:10.1128/JVI.00529-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Li, C., Hirsch, M., DiPrimio, N., Asokan, A., Goudy, K., Tisch, R., Samulski, R. J. (2009). Cytotoxic-T-Lymphocyte-Mediated Elimination of Target Cells Transduced with Engineered Adeno-Associated Virus Type 2 Vector In Vivo. J. Virol. 83: 6817-6824 [Abstract] [Full Text]  
  • Li, C., Goudy, K., Hirsch, M., Asokan, A., Fan, Y., Alexander, J., Sun, J., Monahan, P., Seiber, D., Sidney, J., Sette, A., Tisch, R., Frelinger, J., Samulski, R. J. (2009). Cellular immune response to cryptic epitopes during therapeutic gene transfer. Proc. Natl. Acad. Sci. USA 106: 10770-10774 [Abstract] [Full Text]  
  • Velazquez, V. M., Bowen, D. G., Walker, C. M. (2009). Silencing of T lymphocytes by antigen-driven programmed death in recombinant adeno-associated virus vector-mediated gene therapy. Blood 113: 538-545 [Abstract] [Full Text]  


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