The murine gammaherpesvirus 68 v-cyclin gene is an oncogene that promotes cell cycle progression in primary lymphocytes

Several gammaherpesviruses contain open reading frames encoding proteins ho mologous to mammalian D-type cyclins. In this study, we analyzed the expres sion and function of the murine gammaherpesvirus 68 (gamma HV68) viral cycl in (v-cyclin). The gamma HV68 v-cyclin gene was expressed in lytically infe cted fibroblasts as a leaky-late mRNA of approximately 0.9 kb encoding a pr otein of approximately 25 kDa. To evaluate the effect of the gamma HV68 v-c yclin on cell cycle progression in primary lymphocytes and to determine if the gamma HV68 v-cyclin gene is an oncogene, we generated transgenic mice b y using the lck proximal promoter to express the gamma HV68 v-cyclin in ear ly T cells. Expression of the gamma HV68 v-cyclin significantly increased t he number of thymocytes in cell culture, as determined by measuring both DN A content and incorporation of 5-bromo-2-deoxyuridine following in vivo pul se-labeling. Expression of the gamma HV68 v-cyclin interfered with normal t hymocyte maturation, as shown by increased numbers of CD4(+) CD8(+) double- positive thymocytes and decreased numbers of CD lf or CD8(+) single-positiv e and T-cell-receptor-bright thymocytes and splenocytes in transgenic mice. Despite increased numbers of cycling thymocytes, gamma HV68-v-cyclin-trans genic mice did not have proportionately increased thymocyte numbers, and st aining by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick en d labeling demonstrated increased apoptosis in the thymi of v-cyclin-transg enic mice. Fifteen of 38 gamma HV68-v-cyclin-transgenic mice developed high -grade lymphoblastic lymphoma between 3 and 12 months of age. We conclude t hat (i) the gamma HV68 v-cyclin is expressed as a leaky-late gene in lytica lly infected cells, (ii) expression of the gamma HV68 v-cyclin in thymocyte s promotes cell cycle progression and inhibits normal T-cell differentiatio n, and (iii) the gamma HV68 v-cyclin gene is an oncogene.