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Journal of Virology, June 1999, p. 5110-5122, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The Murine Gammaherpesvirus 68 v-Cyclin Gene Is an Oncogene That Promotes Cell Cycle Progression in Primary Lymphocytes

Linda F. van Dyk,1 Jay L. Hess,2 Jonathan D. Katz,1 Meagan Jacoby,1 Samuel H. Speck,1,* and Herbert W. Virgin IV1,*

Center for Immunology, Departments of Pathology and Molecular Microbiology,1 and Lauren V. Ackerman Laboratory of Surgical Pathology,2 Washington University School of Medicine, St. Louis, Missouri

Received 10 November 1998/Accepted 4 March 1999

Several gammaherpesviruses contain open reading frames encoding proteins homologous to mammalian D-type cyclins. In this study, we analyzed the expression and function of the murine gammaherpesvirus 68 (gamma HV68) viral cyclin (v-cyclin). The gamma HV68 v-cyclin gene was expressed in lytically infected fibroblasts as a leaky-late mRNA of approximately 0.9 kb encoding a protein of approximately 25 kDa. To evaluate the effect of the gamma HV68 v-cyclin on cell cycle progression in primary lymphocytes and to determine if the gamma HV68 v-cyclin gene is an oncogene, we generated transgenic mice by using the lck proximal promoter to express the gamma HV68 v-cyclin in early T cells. Expression of the gamma HV68 v-cyclin significantly increased the number of thymocytes in cell culture, as determined by measuring both DNA content and incorporation of 5-bromo-2-deoxyuridine following in vivo pulse-labeling. Expression of the gamma HV68 v-cyclin interfered with normal thymocyte maturation, as shown by increased numbers of CD4+ CD8+ double-positive thymocytes and decreased numbers of CD4+ or CD8+ single-positive and T-cell-receptor-bright thymocytes and splenocytes in transgenic mice. Despite increased numbers of cycling thymocytes, gamma HV68-v-cyclin-transgenic mice did not have proportionately increased thymocyte numbers, and staining by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling demonstrated increased apoptosis in the thymi of v-cyclin-transgenic mice. Fifteen of 38 gamma HV68-v-cyclin-transgenic mice developed high-grade lymphoblastic lymphoma between 3 and 12 months of age. We conclude that (i) the gamma HV68 v-cyclin is expressed as a leaky-late gene in lytically infected cells, (ii) expression of the gamma HV68 v-cyclin in thymocytes promotes cell cycle progression and inhibits normal T-cell differentiation, and (iii) the gamma HV68 v-cyclin gene is an oncogene.

* Corresponding author. Mailing address: Center for Immunology, Departments of Pathology and Molecular Microbiology, Washington University School of Medicine, Box B118, 660 S. Euclid Ave., St. Louis, MO 63110-1093. Phone for Samuel H. Speck: (314) 362-0367. Fax: (314) 362-4096. E-mail: speck{at}pathbox.wustl.edu. Phone for Herbert W. Virgin IV: (314) 362-9223. Fax: (314) 362-4096. E-mail: virgin{at}immunology.wustl.edu.

Journal of Virology, June 1999, p. 5110-5122, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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Copyright © 1999 by the American Society for Microbiology. All rights reserved.