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Primary adenovirus-specific cytotoxic T lymphocyte response occurs after viral clearance and liver enzyme elevation

Gene Therapy volume 12, pages 1079–1088 (2005)Cite this article

Abstract

The virus-specific cytotoxic T lymphocyte (CTL) response is a major obstacle to effective delivery of adenovirus gene therapy. However, its relative role in viral clearance, transgene elimination and hepatotoxicity remains unclear. In this paper, we present an analysis of viral clearance and liver toxicity in relation to the induction of the virus-specific CD8 T-cell response revealed by an MHC class I tetramer. A surprisingly high number of tetramer+ CD8 T cells were found in the liver and lung and reached peak values at days 8 and 10, respectively, post-infection. Nearly 100% of these tetramer+ CD8 T cells expressed high levels of granzyme B and IFNγ. Remarkably, liver viral load and liver enzyme elevation peaked early, at days 2 and 4, respectively, post-infection, before the specific CTL response was detectable. After generation of CTLs, there was only minimal liver damage or further decrease in virus titer. These results indicated that the primary peak response of tetramer+ CTLs does not correlate with the elimination of adenovirus or liver cytotoxic response.

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Acknowledgements

We thank Dr Fiona Hunter for reviewing the manuscript, Dr Rafi Ahmed for providing critical suggestions, and Carol Humber for excellent secretarial work. This work was supported in part by National Institutes of Health Grants RO1-AI-42900 (to JD Mountz) and RO1-CA-86881 (to DT Curiel), and by a VA Career Development Award and Merit Review Award (to JD Mountz).

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Authors and Affiliations

  1. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    J Chen, H-C Hsu, P Yang, Q Wu, X Xu, X Wang, D T Curiel & J D Mountz

  2. Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA

    A J Zajac

  3. Center for AIDS Research, University of Alabama at Birmingham, Birmingham, AL, USA

    S A McPherson

  4. Department of Pediatric Dentistry, University of Alabama at Birmingham, Birmingham, AL, USA

    K Fujihashi

  5. Department of Pathology and Surgery, University of Alabama at Birmingham, Birmingham, AL, USA

    D T Curiel

  6. Division of Human Gene Therapy and Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL, USA

    D T Curiel

  7. Veteran Administration Medical Center, Birmingham, AL, USA

    J D Mountz

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Chen, J., Zajac, A., McPherson, S. et al. Primary adenovirus-specific cytotoxic T lymphocyte response occurs after viral clearance and liver enzyme elevation. Gene Ther 12, 1079–1088 (2005). https://doi.org/10.1038/sj.gt.3302494

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