Identification of transcription factors with potential therapeutic effect in cells infected by different variants of HPVs 18 and 16

• Grant number: 19/05141-8
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: April 01, 2019
• End date: September 25, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Laura Cristina Sichero Vettorazzo
• Grantee: Valéria Talpe Nunes
• Host Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). Coordenadoria de Serviços de Saúde (CSS). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 17/23211-8 - Impact of genetic variants of HPV on persistence of infection and risk of disease: an epidemiological and functional approach, AP.TEM
• Associated scholarship(s): 23/12249-5 - The role of GATA3 in the regulation of high-risk HPV transcription and differentiation of human keratinocytes, BE.EP.DD

Abstract

Persistent high-risk oncogenic Human Papillomavirus (HPV) infections are associated with the development of Cervical and Vulvar Cancer in women, Penile Cancer in men, and anorectal and oropharyngeal tumors in both sexes. Among this group, HPV-16 is the world's most prevalent type in Cervical Carcinomas, followed by HPV-18. In neoplasms of other anogenital sites and oropharynx, HPV-16 is detected in almost all tumors attributable to HPV. Intra-typical nucleotide variability of some types of HPV has been studied resulting in important findings regarding its phylogeny and evolution. In addition, studies conducted by us and others have shown that in women, specific HPV-16 variants are associated with a higher risk of developing cervical and anal tumors and pre-neoplastic lesions. The region of the HPV genome required for the immortalization of primary human keratinocytes was mapped to the CSF-E6-E7 viral region. Thus, it is reasonable to assume that changes in these regions may affect biological function and consequently the clinical outcome of infections. Transcription and replication of HPV are regulated by binding of cellular and viral proteins to cis-elements in the CSF (long control region). We have observed that variants of the same HPV type show differences in transcriptional activity that can be attributed to differences in binding of both cellular and viral Transcription Factors (FT), since the CSF nucleotide sequence differs by up to 5% between variants of the same viral type. Although these data support a possible implication of genetic heterogeneity of CSF on the pathogenesis of neoplasms associated with HPV infection, knowledge about the regulation of viral gene expression is currently limited. The objective of this project is to: (1) evaluate the effect of a wide range of cellular FTs on the gene expression of early HPV genes 18 and 16; (2) to evaluate among the cellular FTs required for the gene expression of high risk HPVs 16 and 18, those potentially potentially new targets for antiviral therapies. (AU)