Gene Expression of Genital Human Papillomaviruses and Considerations on Potential Antiviral Approaches

Genital human papillomaviruses (HPVs) are carcinogenic to humans and are associated with most cases of cervical cancer, genital and laryngeal warts, and certain cutaneous neoplastic lesions. Five of the more than 50 known genital HPV types, HPV-6, -11, -16, -18 and -31, have become the models to study gene expression. The comparison of the studies of these five viruses and analyses of the genomic sequences of those genital HPV types that have not been transcriptionally studied make it likely that genital HPVs share most strategies for regulating their transcription. These strategies are quite different from those of unrelated human and animal papillomaviruses. Among these common properties are (i) a specific promoter structure allowing for fine-tuned negative feedback, (ii) a transcriptional enhancer that is specific for epithelial cells, (iii) regulation by progesterone and glucocorticoid hormones, (iv) silencers, whose principal function appears to be transcriptional repression in the basal layer of infected epithelia, (v) specifically positioned nucleosomes that mediate the functions of some enhancer and the silencer factors, (vi) nuclear matrix attachment regions that can, under different conditions, repress or stimulate transcription, and (vii) as yet poorly understood late promoters positioned very remote from the late genes. Most of these properties are controlled by cellular proteins that, due to their simultaneous importance for cellular processes, may not be useful as HPV-specific drug targets. It should be possible, however, to target complex cis-responsive elements unique to these HPV genomes by nucleotide sequence-specific molecules, such as antisense RNA, polyamides and artificial transcription factors. The application of small molecule-based drugs may be restricted to target proteins encoded by the HPV DNA, such as the replication factor E1 and the transcription/replication factor E2.