Abstract
Persistent infections by high-risk HPVs (Human Papillomavirus) are associated with the development of Cervical and Vulvar Cancer in women, Penile Cancer in men, and anal and Oropharyngeal Tumors in both gender. Among this group, HPV-16 is worldwide the most prevalent type in Cervical Carcinomas, followed by HPV-18. In neoplasias of other anogenital sites and the oropharynx, HPV-16 is detected in almost all the tumors attributable to HPV. On the other hand, genital warts and the rare but serious Recurrent Respiratory Papillomatosis (RRP) are etiologically associated with low-risk oncogenic HPVs 6 and 11 infections. Due to the importance of these four virus, since 2006 a quadrivalent prophylactic vaccine capable of preventing infection by HPVs 6, 11, 16 and 18 is available. Intra-typical nucleotide variability of some types of HPV has been studied resulting in important findings regarding their phylogeny and evolution. In addition, studies conducted by us and others revealed that specific variants of HPV-16 are associated with a higher risk of developing tumors and pre-neoplastic lesions in the cervix and anal canal of women. On the opposite, there is a gap in the knowledge concerning the impact of HPV-16 variability upon infection persistence and the development of neoplasias at the male anogenital region and the oropharynx in both sexes. Regarding low-risk HPVs, we recently demonstrated that specific variants of HPV-6 are associated to a higher risk of developing genital warts in men, whereas HPV-11 variability does not appear to impact the clinical outcome. A similar study is underway in our laboratory on genital samples from women participating in a prospective study. However, because RRP is a rare disease, data on the prevalence of viral variants of HPVs 6 and 11 and the impact of viral heterogeneity on the clinical variables of this disease are limited to studies enclosing a restricted number of samples. The region of the HPV genome necessary for the immortalization of primary human keratinocytes mapps to the LCR-E6-E7 viral region. Thus, it is reasonable to assume that alterations in these regions can affect the biological function and consequently the clinical outcome of infections. The transcription and replication of HPV are regulated by the binding of cellular and viral proteins to cis-elements in the LCR (long control region). We have observed that variants of the same viral type present differences in transcriptional activity that can be attributed to differences in the binding of Transcription Factors (FT), both viral and cellular, since the LCR nucleotide sequence differs by up to 5% among variants of the same HPV type. Although these data support a possible implication of the genetic heterogeneity of the LCR upon the pathogenesis of neoplasias associated to HPV infections, the knowledge about the regulation of viral gene expression is currently limited. Therefore, this project aims to (1) characterize the impact of viral genetic variability upon HPV persistence and anogenital diseases associated in men, and in extragenital sites of both gender; (2) evaluate de effect of a broad spectrum cellular FTs upon the expression of early genes of HPVs 18, 16, 11 e 6; (3) to evaluate among cellular TFs required for high risk HPVs 16 and 18 gene expression regulation those that could potentially stand as new targets for antiviral therapies; (4) evaluate the transcriptional activity of early promoter of low risk HPVs 6 and 11 during cellular differentiation. This data is crucial to better understand the Biology, Pathogenesis, diagnosis and clinical management of these diseases. (AU)
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