Virus-host interactions in the context of natural human papillomavirus type 16 E6 gene variants

人乳头瘤病毒 *（HPV）是影响人类的最常见微生物感染之一。* 迄今已查明150多种类型。根据人口和年龄，* 高达20%的女性和60%的男性可以携带一种或多种HPV* 类型。HPV感染上呼吸道和肛门生殖道的粘膜组织以及皮肤。它们的基因组编码几种结构和功能蛋白。在某些HPV中，如16型，两种功能蛋白E6和E7协同作用，使感染的宿主细胞永生化和表型转化。然而，E6是推动这些变化的主要影响因素。有HPV 16基因组变体，* 值得注意的是，E6基因比E7基因更具多态性。HPV变异与它们首次被发现的地理区域有关，这表明它们与特定的人群共同进化。我们假设这些 *E6变体影响相应变体E6* 蛋白的性能，这很可能是由于蛋白 * 结构的构象变化。事实上，我们最近的功能研究表明，在2种HPV 16变异体中，E6蛋白N末端的3个氨基酸变化引起了差异转化潜力和在宿主中持续存在的能力：欧洲原型（EP）和亚裔美国人（AA），这两种变异体都经常在美国人群中发现。我们的目标与这个跨学科 * 研究计划，在三个短期目标解决，是了解 * 基因组HPV变异的潜在机制，重点是E6，导致 * 病毒-宿主相互作用的显着变化，影响他们的能力 * 转化感染的宿主细胞。我们将使用几种体外细胞培养模型 *（单层细胞转导单一E6变异基因和3D* 筏培养转染全长HPV 16变异基因组）* 和方法学方法（高通量基因表达分析，包括 * RNA测序，生物信息学，代谢途径表征和 * 蛋白质-蛋白质相互作用调查）来回答我们的研究问题。该研究计划的长期目标是：1）推进基础病毒研究和生物信息学的知识，重点是DNA病毒转化的进化和分子机制，2）提供定制的“生物学家友好”生物信息学软件用于病毒宿主分析，3）提供具有社会，在当今快节奏的科学界取得成功所需的知识和实践技能。我们的成功将由我们 * 研究所强大的跨学科研究环境（分子生物学和病毒学，细胞生物学，生物化学，生物信息学和 * 组织学），建议工作的专业知识，优秀的HQP监督，最先进的设备以及国家和国际合作者来保证。**

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. **