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Journal of Virology, December 2008, p. 12498-12509, Vol. 82, No. 24
0022-538X/08/$08.00+0     doi:10.1128/JVI.01152-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Persistent Gammaherpesvirus Replication and Dynamic Interaction with the Host In Vivo{triangledown}

Seungmin Hwang,1 Ting-Ting Wu,1 Leming M. Tong,1 Kyeong Seon Kim,1 DeeAnn Martinez-Guzman,2 Arnaud D. Colantonio,3 Christel H. Uittenbogaart,3,4 and Ren Sun1,2*

Department of Molecular and Medical Pharmacology,1 Molecular Biology Institute,2 Departments of Microbiology, Immunology and Molecular Genetics,3 Pediatrics, University of California, Los Angeles, Los Angeles, California 900954

Received 3 June 2008/ Accepted 26 September 2008

Gammaherpesviruses establish life-long persistency inside the host and cause various diseases during their persistent infection. However, the systemic interaction between the virus and host in vivo has not been studied in individual hosts continuously, although such information can be crucial to control the persistent infection of the gammaherpesviruses. For the noninvasive and continuous monitoring of the interaction between gammaherpesvirus and the host, a recombinant murine gammaherpesvirus 68 (MHV-68, a gammaherpesvirus 68) was constructed to express a firefly luciferase gene driven by the viral M3 promoter (M3FL). Real-time monitoring of M3FL infection revealed novel sites of viral replication, such as salivary glands, as well as acute replication in the nose and the lung and progression to the spleen. Continuous monitoring of M3FL infection in individual mice demonstrated the various kinetics of transition to different organs and local clearance, rather than systemically synchronized clearance. Moreover, in vivo spontaneous reactivation of M3FL from latency was detected after the initial clearance of acute infection and can be induced upon treatment with either a proteasome inhibitor Velcade or an immunosuppressant cyclosporine A. Taken together, our results demonstrate that the in vivo replication and reactivation of gammaherpesvirus are dynamically controlled by the locally defined interaction between the virus and the host immune system and that bioluminescence imaging can be successfully used for the real-time monitoring of this dynamic interaction of MHV-68 with its host in vivo.

* Corresponding author. Mailing address: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095. Phone: (310) 794-5557. Fax: (310) 794-5123. E-mail: rsun{at}mednet.ucla.edu

{triangledown} Published ahead of print on 8 October 2008.

Journal of Virology, December 2008, p. 12498-12509, Vol. 82, No. 24
0022-538X/08/$08.00+0     doi:10.1128/JVI.01152-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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