Transcriptional activity of cutaneous HPVs

Abstract

The E6 and E7 genes encode the HPV oncoproteins that play a central role in the viral life cycle and malignant transformation. The expression of these oncoproteins depends especially on the activation of the viral promoter contained in the Long Control Region (LCR). In addition, this region contains regulatory elements where cellular Transcription Factors (TFs) bind. The repertoire of TFs that interact with the LCR plays an important role in the oncoprotein transcription activation. In subproject 2, the objective is to evaluate the impact of a wide range of cellular TFs on the early promoter of mucosal HPVs. In this proposal, we intend to expand this objective by integrating the study of cutaneous HPVs transcription into the thematic project. These HPVs, mainly represented by the genus Beta, are widely present on the skin surface in the general population without causing any injury, however, they can induce benign skin lesions in immunocompromised individuals, including cutaneous papillomas and warts. In addition, there is increasing evidence of an etiologic role of human beta papillomaviruses (beta-HPVs) in non-melanoma skin Cancer associated with UV irradiation. However, our knowledge of beta-HPVs biology is still incomplete. In particular, the mechanisms of regulation of cutaneous HPVs gene expression are poorly understood and require further research. Thus, the objective is to carry out the study of the transcription of cutaneous HPVs. Initially, we intend to identify and map the main LCR regulatory elements of beta-HPVs 5, 38, and 49. Then, using a tool with more than 500 cDNA arrays of transcription factors, we aim to identify TFs relevant to promoter activation of these HPVs. The TFs with the greatest effect will be investigated for direct binding to LCR, interaction with other correlated TFs, and for the effects on oncogene expression. Additionally, it is proposed to evaluate the expression of TFs of interest in HPV-positive and negative actinic cheilitis samples. Finally, we intend to investigate the role of TFs in the regulation of transcriptional activity in association with ultraviolet (UV) irradiation. The results generated will contribute to a better understanding of how these viruses interact with host cells in the establishment of the infection, when the activation of oncogene transcription is essential for the success of the viral life cycle. It is believed that among the identified TFs, unexplored possibilities for the diagnosis and treatment of lesions associated with cutaneous HPVs may emerge. (AU)