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Journal of Virology, September 2006, p. 8303-8315, Vol. 80, No. 17
0022-538X/06/$08.00+0     doi:10.1128/JVI.00237-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Gammaherpesvirus Persistence Alters Key CD8 T-Cell Memory Characteristics and Enhances Antiviral Protection

Joshua J. Obar,1 Shinichiro Fuse,1 Erica K. Leung,2 Sarah C. Bellfy,1 and Edward J. Usherwood1*

Department of Microbiology and Immunology, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, New Hampshire 03756,1 Honors Biology and Pharmacology Program, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4L8, Canada2

Received 2 February 2006/ Accepted 7 June 2006

In herpesvirus infections, the virus persists for life but is contained through T-cell-mediated immune surveillance. How this immune surveillance operates is poorly understood. Recent studies of other persistent infections have indicated that virus persistence is associated with functional deficits in the CD8+ T-cell response. To test whether this is the case in a herpesvirus infection, we used a mutant murine gammaherpesvirus that is defective in its ability to persist in the host. By comparing the immune response to this virus with a revertant virus that can persist, we were able to dissect the changes in the antiviral CD8+ T-cell response that are induced by virus persistence. Surprisingly, persistently infected mice controlled a secondary challenge infection more rapidly than nonpersistently infected mice, indicating enhanced rather than diminished effector functions. Consistent with this, virus-specific CD8 T cells from these mice exhibited faster upregulation of the cytotoxic mediator granzyme B. Another unexpected finding was that CD8+ T cells from neither infection responded efficiently to homeostatic cytokines. The unresponsiveness of the memory cells from the nonpersistently infected mice appears to be linked to the prolonged replication of virus within the lungs. Other changes seen in different chronic infection models were also observed, such as changes in Bcl-2 levels, interleukin-2 production, and the immunodominance hierarchy. These data show persistence of gammaherpesvirus type 68 alters the properties of CD8+ T cells and illustrates that immune surveillance does not require CD8 T cells with the same attributes as "classical" memory CD8+ T cells.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, 1 Medical Center Drive, Lebanon, NH 03756. Phone: (603) 650-7730. Fax: (603) 650-6223. E-mail: EJU{at}dartmouth.edu.

Journal of Virology, September 2006, p. 8303-8315, Vol. 80, No. 17
0022-538X/06/$08.00+0     doi:10.1128/JVI.00237-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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