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Immune Control of the Number and Reactivation Phenotype of Cells Latently Infected with a Gammaherpesvirus

Scott A. Tibbetts,¹ Linda F. van Dyk,^1, Samuel H. Speck,^2* and Herbert W. Virgin, IV^2*

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

Received 13 February 2002/ Accepted 16 April 2002

Despite active immune responses, gammaherpesviruses establish latency. In a related process, these viruses also persistently replicate by using a mechanism that requires different viral genes than acute-phase replication. Many questions remain about the role of immunity in chronic gammaherpesvirus infection, including whether the immune system controls latency by regulating latent cell numbers and/or other properties and what specific immune mediators control latency and persistent replication. We show here that CD8⁺ T cells regulate both latency and persistent replication and demonstrate for the first time that CD8⁺ T cells regulate both the number of latently infected cells and the efficiency with which infected cells reactivate from latency. Furthermore, we show that gamma interferon (IFN-) and perforin, which play no significant role during acute infection, are essential for immune control of latency and persistent replication. Surprisingly, the effects of perforin and IFN- are site specific, with IFN- being important in peritoneal cells while perforin is important in the spleen. Studies of the mechanisms of action of IFN- and perforin revealed that perforin acts primarily by controlling the number of latently infected cells while IFN- acts primarily by controlling reactivation efficiency. The immune system therefore controls chronic gammaherpesvirus infection by site-specific mechanisms that regulate both the number and reactivation phenotype of latently infected cells.

* 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.

Present address: Department of Microbiology, University of Colorado Health Science Center, Denver, CO 80262.

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