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Journal of Virology, August 2005, p. 10619-10626, Vol. 79, No. 16
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.16.10619-10626.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

CD8+ T-Cell Dysfunction due to Cytolytic Granule Deficiency in Persistent Friend Retrovirus Infection

Gennadiy Zelinskyy,1 Shelly J. Robertson,2 Simone Schimmer,1 Ronald J. Messer,2 Kim J. Hasenkrug,2,{dagger} and Ulf Dittmer1,{dagger}*

Institut fuer Virologie des Universitaetsklinikums Essen, Essen, Germany,1 Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana2

Received 18 January 2005/ Accepted 20 May 2005

Virus-specific CD8+ T cells are critical for the control of acute Friend virus (FV) infections, but are rendered impotent by CD4+ regulatory T cells during the chronic phase of infection. The current study examines this CD8+ T-cell dysfunction by analyzing the production and release of cytolytic molecules by CD8+ T cells. CD8+ T cells with an activated phenotype (CD43+) from acutely infected mice produced all three key components of lytic granules: perforin, granzyme A, and granzyme B. Furthermore, they displayed evidence of recent degranulation and in vivo cytotoxicity. In contrast, activated CD8+ T cells from chronically infected mice were deficient in cytolytic molecules and showed little evidence of recent degranulation and poor in vivo cytotoxicity. Evidence from tetramer-positive CD8+ T cells with known virus specificity confirmed the findings from the activated subset of CD8+ T cells. Interestingly, perforin and granzyme A mRNA levels were not significantly reduced during chronic infection, indicating control at a posttranscriptional level. Granzyme B deficiency was associated with a significant decrease in mRNA levels, but posttranscriptional control also appeared to contribute to deficiency. These results demonstrate a broad impairment of cytotoxic CD8+ T-cell effector function during chronic retroviral infection and explain the inability of virus-specific CD8+ T cells to eliminate persistent virus.

* Corresponding author. Mailing address: Institut fuer Virologie, Universitaetsklinikum Essen, 45122 Essen, Germany. Phone: 49(201) 7233693. Fax: +49(201) 723-5929. E-mail:ulf.dittmer{at}uni-essen.de.

{dagger} Both authors contributed equally to the design and documentation of this study.

Journal of Virology, August 2005, p. 10619-10626, Vol. 79, No. 16
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.16.10619-10626.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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