Grant: Discovery Grants Program - Individual

Human papillomavirus(HPV) is one of the most common microbial infections affecting humans. Morethan 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 HPVtypes. HPVs infect mucosal tissues of the upper respiratory and anogenitaltracts as well as the skin. Their genomes encode several structural andfunctional proteins. In certain HPVs such as type 16, two functional proteins,E6 and E7, act synergistically to immortalize and andphenotypically transform infected host cells. However, E6 isthe 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 beenlinked to the geographical region where they were first found, suggesting thatthey have co-evolved with specific human populations. We hypothesize that theseE6 variants influence the performance of the corresponding variant E6proteins, which is most likely due to conformational changes in proteinstructure. Indeed, our most recent functional studies suggest differentialtransforming potential and ability to persist in the host caused by just 3amino acid changes in the N-terminus of the E6 protein in 2 HPV16 variants: EuropeanPrototype (EP) and Asian American (AA), both of which are frequently found in American populations. Our goal with this inter-disciplinaryresearch program, addressed in three short-term objectives, is to understandthe underlying mechanisms of how genomic HPV variants, with focus on E6, causesignificant changes in virus-host interactions which affect their ability totransform infected host cells. We will use several in vitro cell culture models(monolayer cells transduced with single E6 variant genes and 3Draft cultures transfected with either of the full-length HPV16 variant genomes)and methodological approaches (high-throughput gene expression analyses includingRNA-sequencing, bioinformatics, metabolic pathway characterization andprotein-protein interaction surveys) to answer our research questions. Thelong-term objectives of this research program will be to 1) advance knowledge inbasic virus research and bioinformatics, with a focus on the evolution andmolecular 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 beguaranteed by the strong inter-disciplinary research environment at ourinstitute (molecular biology and virology, cell biology, biochemistry, bioinformatics andhistology), expertise in the work proposed, excellent HQP supervision, state-of-the-artequipment as well as national and international collaborators.