The papillomaviruses are small DNA tumor viruses which cause benign and malignant lesions of squamous epithelia in higher vertebrates. The complete lytic cycle of these viruses occurs only in the differentiated keratinocytes of a squamous epithelium. Bovine papillomavirus type 1 (BPV-1) was used as a model system for the study of the regulation of papillomavirus gene expression by keratinocyte differentiation. In situ hybridization studies using sections of bovine fibropapillomas and mRNA specific oligonucleotide probes demonstrated that the splicing of BPV-1 late pre-mRNAs is regulated in a differentiation specific manner. Other posttranscriptional regulatory mechanisms also control late gene expression. Sequences in the 5' untranslated regions (UTR) of the BPV-1 major capsid protein (L1) mRNA have been shown to affect translation of this protein. In addition, a cis-acting regulatory element which inhibits late gene expression has been identified in the late 3' UTR of BPV-1 and human papillomavirus type 16 (HPV-16). This element has been characterized as a 5' splice site and shown to bind the splicing factor U1 snRNP. The function of this element appears to be inhibition of polyadenylation rather than splicing, however. The activity of this element was shown to be blocked by the human immunodeficiency type 1 (HIV-1) Rev protein, raising the possibility that viral and/or cellular Rev-like proteins may control the activity of the papillomavirus late 3'UTR elements. A nonconsensus 5' splice site in the BPV-1 early region has also been shown to be important in the regulation of early versus late poly(A) site choice. This system was used to further investigate the mechanism of inhibition of gene expression by 5' splice sites. Using in vivo transfection experiments and competition with a cis- acting hammerhead ribozyme, a consensus 5' splice site was shown to inhibit polyadenylation. Furthermore, a 5' splice site had no effect on an alternative mechanism of mRNA 3' end formation used by histone mRNAs or on nucleocytoplasmic transport of mRNAs processed by histone 3' end formation, demonstrating the specificity of this interaction.
