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.