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Journal of Virology, June 2007, p. 6134-6140, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.00108-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Gamma Interferon Blocks Gammaherpesvirus Reactivation from Latency in a Cell Type-Specific Manner{triangledown}

Ashley Steed,1 Thorsten Buch,3 Ari Waisman,2 and Herbert W. Virgin IV1*

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110,1 I. Medical Department, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany,2 Department of Experimental Neuroimmunology, University of Zurich, CH-8057 Zurich, Switzerland3

Received 16 January 2007/ Accepted 6 March 2007

Gammaherpesviruses are important pathogens whose lifelong survival in the host depends critically on their capacity to establish and reactivate from latency, processes regulated by both viral genes and the host immune response. Previous work has demonstrated that gamma interferon (IFN-{gamma}) is a key regulator of chronic infection with murine gammaherpesvirus 68 ({gamma}HV68), a virus that establishes latent infection in B lymphocytes, macrophages, and dendritic cells. In mice deficient in IFN-{gamma} or the IFN-{gamma} receptor, {gamma}HV68 gene expression is altered during chronic infection, and peritoneal cells explanted from these mice reactivate more efficiently ex vivo than cells derived from wild-type mice. Furthermore, treatment with IFN-{gamma} inhibits reactivation of {gamma}HV68 from latently infected wild-type peritoneal cells, and depletion of IFN-{gamma} from wild-type mice increases the efficiency of reactivation of explanted peritoneal cells. These profound effects of IFN-{gamma} on chronic {gamma}HV68 latency and reactivation raise the question of which cells respond to IFN-{gamma} to control chronic {gamma}HV68 infection. Here, we show that IFN-{gamma} inhibited reactivation of peritoneal cells and spleen cells harvested from mice lacking B lymphocytes, but not wild-type spleen cells, suggesting that IFN-{gamma} may inhibit reactivation in a cell type-specific manner. To directly test this hypothesis, we expressed the diphtheria toxin receptor specifically on either B lymphocytes or macrophages and used diphtheria toxin treatment to deplete these specific cells in vivo and in vitro after establishing latency. We demonstrate that macrophages, but not B cells, are responsive to IFN-{gamma}-mediated suppression of {gamma}HV68 reactivation. These data indicate that the regulation of gammaherpesvirus latency by IFN-{gamma} is cell type specific and raise the possibility that cell type-specific immune deficiency may alter latency in distinct and important ways.

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

{triangledown} Published ahead of print on 14 March 2007.

Journal of Virology, June 2007, p. 6134-6140, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.00108-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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