Grant: Discovery Grants Program - Individual

Human papillomavirus*(HPV) is one of the most common microbial infections affecting humans. More*than 150 types have been identified to date. Depending on population and age,*up to 20% of females and 60% of males can harbour one or more HPV*types. HPVs infect mucosal tissues of the upper respiratory and anogenital*tracts as well as the skin. Their genomes encode several structural and*functional proteins. In certain HPVs such as type 16, two functional proteins,*E6 and E7, act synergistically to immortalize and and*phenotypically transform infected host cells. However, E6 is*the main effecter driving these changes. There are HPV16 genome variants and,*notably, the E6 gene is more polymorph than the E7 gene. HPV variants have been*linked to the geographical region where they were first found, suggesting that*they have co-evolved with specific human populations. We hypothesize that these*E6 variants influence the performance of the corresponding variant E6*proteins, which is most likely due to conformational changes in protein*structure. Indeed, our most recent functional studies suggest differential*transforming potential and ability to persist in the host caused by just 3*amino acid changes in the N-terminus of the E6 protein in 2 HPV16 variants: European*Prototype (EP) and Asian American (AA), both of which are frequently found in American populations. Our goal with this inter-disciplinary*research program, addressed in three short-term objectives, is to understand*the underlying mechanisms of how genomic HPV variants, with focus on E6, cause*significant changes in virus-host interactions which affect their ability to*transform infected host cells. We will use several in vitro cell culture models*(monolayer cells transduced with single E6 variant genes and 3D*raft cultures transfected with either of the full-length HPV16 variant genomes)*and methodological approaches (high-throughput gene expression analyses including*RNA-sequencing, bioinformatics, metabolic pathway characterization and*protein-protein interaction surveys) to answer our research questions. The*long-term objectives of this research program will be to 1) advance knowledge in*basic virus research and bioinformatics, with a focus on the evolution and*molecular mechanisms of transforming DNA viruses, 2) offer custom*""biologist-friendly"" bioinformatics software for virus-host analyses and 3) provide versatile highly qualified personnel (HQP) who have the social, intellectual and hands-on skills required to be successful in today's fast paced scientific community. Our success will be*guaranteed by the strong inter-disciplinary research environment at our*institute (molecular biology and virology, cell biology, biochemistry, bioinformatics and*histology), expertise in the work proposed, excellent HQP supervision, state-of-the-art*equipment as well as national and international collaborators. *