The latency-related gene of bovine herpesvirus 1 inhibits programmed cell death

Although viral gene expression occurs in the peripheral nervous system duri ng acute infection, bovine herpesvirus 1 (BHV-1) gene expression is extingu ished, many neurons survive, and latency ensues. The only abundant viral tr anscript expressed during latency is the latency-related (LR) RNA, which is alternatively spliced in trigeminal ganglia during acute infection (L. Dev ireddy and C, Jones, J, Virol. 72:7294-7301, 1998), A subset of neurons exp ress a protein encoded by the LR gene and the LR protein (LRP) is associate d with cyclin-dependent kinase 2 (Cdk2)/cyclin complexes during productive infection (Y. Jiang, A. Hossain, M. T. Winkler, T. Holt, A. Doster, and C. Jones, J. Virol, 72:8133-8142, 1998). LR gene products inhibit cell cycle p rogression, perhaps as a result of LRP interacting with Cdk2/cyclin complex es, During acute infection, expression of cyclin A occurs in trigeminal gan glionic neurons (L, M. Schang, A. Hossain, and C, Jones, J. Virol, 70:3807- 3814, 1996). Inappropriate expression of G(1)- and S-phase cyclins can init iate programmed cell death (PCD), apoptosis, in neurons, suggesting that LR gene products inhibit PCD, To test this hypothesis, we modified an assay t o measure PD frequency in transiently transfected cells. C-6-ceramide, fumo nisin B-1 (FB1), or etoposide was used to initiate PCD following transfecti on of cells with plasmids expressing LR gene products and the beta-galactos idase gene,Transfected cells that survived were quantified by counting beta -galactosidase-positive cells. Plasmids that expressed LR gene products pro moted survival of monkey kidney (CV-1), human lung (IMR-90), or mouse neuro blastoma (neuro-2A) cells after induction of PCD, Plasmids with termination codons at the beginning of LR open reading frames or deletion of sequences that mediate splicing of LR RNA did not promote cell survival following PC D induction. We hypothesize that LR gene products play a role in promoting survival of postmitotic neurons during acute infection or reactivation.