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Journal of Virology, December 2005, p. 14668-14679, Vol. 79, No. 23
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.23.14668-14679.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Murine Gammaherpesvirus 68 Infection Is Associated with Lymphoproliferative Disease and Lymphoma in BALB ß2 Microglobulin-Deficient Mice

Vera L. Tarakanova,1,{dagger} Felipe Suarez,1,{dagger} Scott A. Tibbetts,1 Meagan A. Jacoby,1 Karen E. Weck,1 Jay L. Hess,2 Samuel H. Speck,3 and Herbert W. Virgin IV1*

Department of Pathology and Immunology and Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110,1 Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104,2 Division of Microbiology and Immunology and The Center for Emerging Infectious Disease, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia 303293

Received 14 July 2005/ Accepted 12 September 2005

Human gammaherpesvirus infections are associated with development of lymphoproliferative disease. Understanding of the mechanisms of gammaherpesvirus lymphomagenesis during chronic infection in a natural host has been limited by the exquisite species specificity of human gammaherpesviruses and the expense of primates. Murine gammaherpesvirus {gamma}HV68 is genetically and biologically related to human gammaherpesviruses and herpesvirus saimiri and has been reported to be associated with lymphoproliferative disease in mice (N. P. Sunil-Chandra, J. Arno, J. Fazakerley, and A. A. Nash, Am. J. Pathol. 145:818-826, 1994). We report the development of an animal model of {gamma}HV68 lymphomagenesis in BALB/c ß2 microglobulin-deficient mice (BALB ß2m–/–). {gamma}HV68 infection induced two lymphoproliferative lesions: B-cell lymphoma and atypical lymphoid hyperplasia (ALH). ALH lesion histology resembled lesions of Epstein-Barr virus-associated posttransplant lymphoproliferative disease and was characterized by the abnormal infiltration of the white pulp with cells expressing the plasma cell marker CD138. Lymphomas observed in {gamma}HV68-infected animals were B220+/CD3– large-cell lymphomas. {gamma}HV68-infected cells were common in ALH lesions as measured by in situ hybridization with a probe specific for viral tRNAs (vtRNAs), but they were scarce in {gamma}HV68-infected spleens with normal histology. Unlike ALH lesions, {gamma}HV68 vtRNA-positive cells were rare in lymphomas. {gamma}HV68 infection of BALB ß2m–/– mice results in lymphoproliferation and lymphoma, providing a valuable tool for identifying viral and host genes involved in gammaherpesvirus-associated malignancies. Our findings suggest that {gamma}HV68 induces lymphomas via hit-and-run oncogenesis, paracrine effects, or stimulation of chronic inflammation.

* Corresponding author. Mailing address: Department of Pathology and Immunology, Washington University, 660 S. Euclid Ave, Box 8118, St. Louis, MO, 63110. Phone: (314) 362-9223. Fax: (314) 362-0369. E-mail: virgin{at}wustl.edu.

{dagger} V.L.T. and F.S. contributed equally to this study.

Journal of Virology, December 2005, p. 14668-14679, Vol. 79, No. 23
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.23.14668-14679.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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