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Journal of Virology, November 2005, p. 14149-14160, Vol. 79, No. 22
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.22.14149-14160.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Alpha/Beta Interferons Regulate Murine Gammaherpesvirus Latent Gene Expression and Reactivation from Latency

Erik S. Barton,1 Mary L. Lutzke,2,{dagger} Rosemary Rochford,2 and Herbert W. Virgin IV1*

Department of Pathology and Immunology and Department of Molecular Microbiology, Washington University School of Medicine, Campus Box 8118, 660 S. Euclid Avenue, St. Louis, Missouri 63110,1 Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York 132102

Received 16 May 2005/ Accepted 29 August 2005

Alpha/beta interferon (IFN-{alpha}/ß) protects the host from virus infection by inhibition of lytic virus replication in infected cells and modulation of the antiviral cell-mediated immune response. To determine whether IFN-{alpha}/ß also modulates the virus-host interaction during latent virus infection, we infected mice lacking the IFN-{alpha}/ß receptor (IFN-{alpha}/ßR–/–) and wild-type (wt; 129S2/SvPas) mice with murine gammaherpesvirus 68 ({gamma}HV68), a lymphotropic gamma-2-herpesvirus that establishes latent infection in B cells, macrophages, and dendritic cells. IFN-{alpha}/ßR–/– mice cleared low-dose intranasal {gamma}HV68 infection with wt kinetics and harbored essentially wt frequencies of latently infected cells in both peritoneum and spleen by 28 days postinfection. However, latent virus in peritoneal cells and splenocytes from IFN-{alpha}/ßR–/– mice reactivated ex vivo with >40-fold- and 5-fold-enhanced efficiency, respectively, compared to wt cells. Depletion of IFN-{alpha}/ß from wt mice during viral latency also significantly increased viral reactivation, demonstrating an antiviral function of IFN-{alpha}/ß during latency. Viral reactivation efficiency was temporally regulated in both wt and IFN-{alpha}/ßR–/– mice. The mechanism of IFN-{alpha}/ßR action was distinct from that of IFN-{gamma}R, since IFN-{alpha}/ßR–/– mice did not display persistent virus replication in vivo. Analysis of viral latent gene expression in vivo demonstrated specific upregulation of the latency-associated gene M2, which is required for efficient reactivation from latency, in IFN-{alpha}/ßR–/– splenocytes. These data demonstrate that an IFN-{alpha}/ß-induced pathway regulates {gamma}HV68 gene expression patterns during latent viral infection in vivo and that IFN-{alpha}/ß plays a critical role in inhibiting viral reactivation during latency.

* Corresponding author. Mailing address: Washington University Medical School, Campus Box 8118, 660 S. Euclid Ave., St. Louis, MO 63110. Phone: (314) 362-9223. Fax: (314) 362-4096. E-mail: virgin{at}wustl.edu.

{dagger} Present address: Kent County Health Department, 700 Fuller Avenue NE, Grand Rapids, MI 49503.

Journal of Virology, November 2005, p. 14149-14160, Vol. 79, No. 22
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.22.14149-14160.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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