Mechanistic Investigations of Ethnic Differences in HPV Variants

描述(由申请人提供)：HPV16的基因变异被定义为主要衣壳蛋白基因相对于原型基因组的差异小于2%已在世界范围内被发现。大量的流行病学和临床数据表明，HPV16变异与宫颈肿瘤的临床进展和侵袭性的差异有关。在世界各地的人群中都发现了来自所有主要HPV16变异谱系的代表性变异，尽管具体的流行情况因地理而异。特定HPV变异体的感染和致癌性似乎因地理和所研究人口的种族来源而异。不同血统的最大预测者是种族。变种，特别是那些与非洲人或亚洲人后裔相关的变种更容易坚持下去。人们试图将HPV16变种在临床表现上的差异与生物学和生命周期联系起来 病毒的特征。然而，这些研究中的大多数都是孤立地分析病毒特定基因或区域的功能，如E6基因产物或上调控区。为了明确地评估因果遗传效应，需要进行全基因组分析。目前还没有关于病毒生命周期和传染性的全基因组研究，以及这可能与种族有关的研究。我们在体外复制完整病毒生命周期的能力，包括产生传染性病毒，使我们能够提出对HPV16变种的全基因组分析。我们还拥有工具和专业知识来研究HPV16变种与种族特定宿主组织的相互作用。我们的长期目标是通过全基因组分析了解HPV变异的种族差异，包括感染流行率和致癌性。据我们所知，这将是第一次对任何HPV变种进行全基因组分析。该提案的具体目标是将欧洲的HPV16变异与两个非洲HPV16变异群(非洲-1和非洲-2)以及亚裔美国人变异群进行比较。中心假设是，种族相关变异在传染性和致癌性方面存在机械差异，这些差异在与该变异相关的种族背景的个体的上皮组织中尤其明显。我们将在三个具体目标下进行这些研究：具体目标1：调查种族特定的HPV16变种致癌倾向的差异。具体目的2：比较人乳头瘤病毒16型变异株民族特异性角质形成细胞的感染性。具体目标3：确定导致HPV16变种特定种族生物学差异的遗传决定因素。

DESCRIPTION (provided by applicant): Genotypic variants of HPV16 are defined as having less than 2% differences in the major capsid protein gene with respect to the prototype genome have been identified worldwide. A body of epidemiological and clinical data has emerged associating groups of HPV16 variants with differences in the clinical progression and aggressiveness of the cervical neoplasia. Representative variants from all major HPV16 variant lineages are detected in populations worldwide, although specific prevalences differ by geography. Infection and oncogenicity of specific HPV variants appears to vary geographically and also with the ethnic origin of the population studied. The greatest predictor of variant lineage is race. Variants, especially those associated with ethnic populations of African or Asian descent have a greater predisposition for persistence. Attempts have been made to correlate the differences in the clinical picture exhibited by HPV16 variants with the biology and life cycle of the virus. However, the majority of these studies have analyzed functions of specific genes or regions of the virus in isolation, such as the E6 gene product or the upper regulatory region. To unequivocally evaluate causal genetic effects, whole-genomes analyses are needed. There have been no whole-genome studies relating to the viral life cycle and infectivity, and how this may be related to the ethnicity. Our ability to reproduce in vitro the complete viral life cycle, including production of infectious virus, places us in a position to propose whole-genome analyses of the HPV16 variants. We also have the tools and expertise to investigate interaction of HPV16 variants with ethnic-specific host tissues. Our long-term goal is to understand ethnic differences in HPV variants using a whole-genome analyses, including infection prevalence and carcinogenicity. As far as we can tell this will be the first whole-genome analyses of any HPV variant. The specific objectives of this proposal are to compare European HPV16 variants with the two African HPV16 variant groups (African-1 and African-2) and the Asian American variant group. The central hypothesis is that ethnic associated variants differ mechanistically in infectivity and carcinogenicity and that these differences are especially acute in epithelial tissus of individuals of the ethnic backgrounds associated with the variant. We will pursue these studies in three specific aims: Specific Aim 1: Investigate differences in the carcinogenic proclivity of ethnic-specific HPV16 variants. Specific Aim 2: Compare infectivity of HPV16 variants ethnic-specific keratinocytes. Specific Aim 3: Identify genetic determinants responsible for ethnic-specific biological differences of HPV16 variants.