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Journal of Virology, February 2005, p. 2573-2583, Vol. 79, No. 4
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.4.2573-2583.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

An Optimized CD8+ T-Cell Response Controls Productive and Latent Gammaherpesvirus Infection

Douglas C. Braaten,1 Rebecca L. Sparks-Thissen,1 Scott Kreher,1 Samuel H. Speck,1,2,{dagger} and Herbert W. Virgin IV1,2*

Departments of Pathology and Immunology,1 Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri2

Received 3 June 2004/ Accepted 1 October 2004

Strategies to prime CD8+ T cells against Murine gammaherpesvirus 68 ({gamma}HV68; MHV68) latency have, to date, resulted in only limited effects. While early forms of latency (<21 days) were significantly reduced, effects were not seen at later times, indicating loss of control by the primed CD8+ T cells. In the present study, we evaluated CD8+ T cells in an optimized system, consisting of OTI T-cell-receptor (TCR) transgenic mice, which generate clonal CD8+ T cells specific for Kb-SIINFEKL of OVA, and a recombinant {gamma}HV68 that expresses OVA ({gamma}HV68.OVA). Our aim was to test whether this optimized system would result in more effective control not only of acute infection but also of later forms of latent infection than was seen with previous strategies. First, we show that OTI CD8+ T cells effectively controlled acute replication of {gamma}HV68.OVA in liver, lung, and spleen at 8 and 16 days after infection of OTI/RAG mice, which lack expression of B and CD4+ T cells. However, we found that, despite eliminating detectable acute replication, the OTI CD8+ T cells did not prevent the establishment of latency in the OTI/RAG mice. We next evaluated the effectiveness of OTI T cells in OTI/B6 animals, which express B cells—a major site of latency in wild-type mice—and CD4+ T cells. In OTI/B6 mice OTI CD8+ T cells not only reduced the frequency of cells that reactivate from latency and the frequency of cells bearing the viral genome at 16 days after infection (similar to what has been reported before) but also were effective at reducing latency at 42 days after infection. Together, these data show that CD8+ T cells are sufficient, in the absence of B cells and CD4+ T cells, for effective control of acute replication. The data also demonstrate for the first time that a strong CD8+ T-cell response can limit long-term latent infection.

* Corresponding author. Mailing address: Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid, Box 8118, St. Louis, MO 63110. Phone: (314) 362-9223. Fax: (314) 362-4096. E-mail: virgin{at}immunology.wustl.edu.

{dagger} Present address: Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329.

Journal of Virology, February 2005, p. 2573-2583, Vol. 79, No. 4
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.4.2573-2583.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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