Technical Abstract: Infection of susceptible animals with bovine viral diarrhea viruses (BVDV) can result in an array of disease symptoms that are dependent on the strain of infecting virus and the physiological status of the host. Cytopathic BVDV kill cells outright while noncytopathic strains can readily establish persistent infections. The molecular mechanisms behind these affects are unknown. To gain a better understanding of the mechanisms of disease, serial analysis of gene expression (SAGE), a powerful method for global gene expression analysis, was employed to examine gene expression changes in BL3 cells, a bovine B-cell lymphosarcoma cell line, following infection with BVDV2. SAGE libraries were constructed from mRNA derived from BL3 cells that were noninfected or infected with the cytopathic BVDV2 strain 296c. Analysis of the SAGE data showed the expression of many of the genes that are characteristic of B cells and integral to their function. Comparison of the SAGE databases also revealed a number of genes that were differentially expressed. Of particular interest was the increased numbers of transcripts encoding proto-oncogenes (c-fos, c-jun, junB, junD) in 296c-infected cells, all of which are constituents of the AP-1 transcriptional activation complex. Real-time RT-PCR confirmed these results and indicated that the actual increase was larger than that indicated by SAGE. Interestingly, there was no corresponding increase in protein levels, but rather a significant decrease of c-jun and junB protein levels in the infected BL3 cells. Rather than an increase in transcription of these genes, it appeared that the transcripts encoding these proto-oncogenes accumulate in the BVDV2-infected cells.