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Journal of Virology, July 2005, p. 8960-8968, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.8960-8968.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Low CD8 T-Cell Proliferative Potential and High Viral Load Limit the Effectiveness of Therapeutic Vaccination

E. John Wherry,1* Joseph N. Blattman,2 and Rafi Ahmed1*

Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, 1510 Clifton Road, Room G211, Atlanta, Georgia 30322,1 Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, P. O. Box 19024, D3-100, Seattle, WA 98109-10242

Received 28 December 2004/ Accepted 17 March 2005

Therapeutic vaccination has the potential to boost immune responses and enhance viral control during chronic infections. However, many therapeutic vaccination approaches have fallen short of expectations, and effective boosting of antiviral T-cell responses is not always observed. To examine these issues, we studied the impact of therapeutic vaccination, using a murine model of chronic infection with lymphocytic choriomeningitis virus (LCMV). Our results demonstrate that therapeutic vaccination using a recombinant vaccinia virus expressing the LCMV GP33 CD8 T-cell epitope can be effective at accelerating viral control. However, mice with lower viral loads at the time of vaccination responded better to therapeutic vaccination than did those with high viral loads. Also, the proliferative potential of GP33-specific CD8 T cells from chronically infected mice was substantially lower than that of GP33-specific memory CD8 T cells from mice with immunity to LCMV, suggesting that poor T-cell expansion may be an important reason for suboptimal responses to therapeutic vaccination. Thus, our results highlight the potential positive effects of therapeutic vaccination on viral control during chronic infection but also provide evidence that a high viral load at the time of vaccination and the low proliferative potential of responding T cells are likely to limit the effectiveness of therapeutic vaccination.

* Corresponding author. Mailing address for R. Ahmed: Emory Vaccine Center, Emory University School of Medicine, 1510 Clifton Road, Room G211, Atlanta, GA 30322. Phone: (404) 727-4700. Fax: (404) 727-3722. E-mail: ra{at}microbio.emory.edu. Present address for E. J. Wherry: Immunology Program, The Wistar Institute, 3601 Spruce Street, Room 251, Philadelphia, PA 19104. Phone: (215) 495-6825. Fax: (215) 495-6817. E-mail: jwherry{at}wistar.upenn.edu.

Journal of Virology, July 2005, p. 8960-8968, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.8960-8968.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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