The Journal of Experimental Medicine
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Published 1 April 2002. doi:10.1084/jem.20011825
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© Rockefeller University Press, 0022-1007/2002/4/931/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 7, April 1, 2002 931-940

Original Article

 Identification of the In Vivo Role of a Viral bcl-2

Shivaprakash Gangappa1, Linda F. van Dyk1, Travis J. Jewett2, Samuel H. Speck3 and Herbert W. Virgin, IV1,2

1 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
2 Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110
3 Division of Microbiology and Immunology, Yerkes Regional Primate Research Center, Emory University, Atlanta, GA 30329

Address correspondence to H.W. Virgin, Department of Pathology and Immunology, Washington University School of Medicine, Box 8118, 660 South Euclid Ave., Phone: 314-362-9223; Fax: 314-362-4096; E-mail: virgin{at}immunology.wustl.edu or S.H. Speck, Division of Microbiology and Immunology, Yerkes Regional Primate Research Center, Emory University, Atlanta, GA 30329. Phone: 404-727-7665; Fax: 404-727-7768; E-mail: sspeck{at}rmy.emory.edu

Many {gamma}-herpesviruses encode candidate oncogenes including homologues of host bcl-2 and cyclin proteins (v-bcl-2, v-cyclin), but the physiologic roles of these genes during infection are not known. We show for the first time in any virus system the physiologic role of v-bcl-2. A {gamma}-herpesvirus v-bcl-2 was essential for efficient ex vivo reactivation from latent infection, and for both persistent replication and virulence during chronic infection of immunocompromised (interferon [IFN]-{gamma}-/-) mice. The v-cyclin was also critical for the same stages in pathogenesis. Strikingly, while the v-bcl-2 and v-cyclin were important for chronic infection, these genes were not essential for viral replication in cell culture, viral replication during acute infection in vivo, establishment of latent infection, or virulence during acute infection. We conclude that v-bcl-2 and v-cyclin have important roles during latent and persistent {gamma}-herpesvirus infection and that herpesviruses encode genes with specific roles during chronic infection and disease, but not acute infection and disease. As {gamma}-herpesviruses primarily cause human disease during chronic infection, these chronic disease genes may be important targets for therapeutic intervention.

Key Words: viral genes • viral latency • reactivation • persistent replication • chronic infection


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