Mechanistic Investigations of Ethnic Differences in HPV Variants

描述（由申请方提供）：HPV 16的基因型变异体定义为主要衣壳蛋白基因与原型基因组的差异小于2%，已在全球范围内鉴定。大量的流行病学和临床数据表明，HPV 16变异体与宫颈肿瘤的临床进展和侵袭性存在差异。在全球人群中检测到来自所有主要HPV16变异谱系的代表性变体，尽管具体患病率因地理而异。特定HPV变异体的感染和致癌性似乎在地理上以及所研究人群的种族来源方面有所不同。变异血统的最大预测因素是种族。变异体，特别是与非洲或亚洲血统的种族人口有关的变异体，具有更大的持久性倾向。已经尝试将HPV16变异体表现出的临床表现差异与生物学和生命周期相关联 病毒。然而，这些研究中的大多数分析了分离的病毒的特定基因或区域的功能，例如E6基因产物或上部调控区。为了明确评估因果遗传效应，需要进行全基因组分析。目前还没有关于病毒生命周期和感染性的全基因组研究，以及这与种族的关系。我们能够在体外复制完整的病毒生命周期，包括感染性病毒的产生，这使我们能够提出HPV16变体的全基因组分析。我们还拥有研究HPV16变异体与种族特异性宿主组织相互作用的工具和专业知识。我们的长期目标是使用全基因组分析来了解HPV变异的种族差异，包括感染率和致癌性。据我们所知，这将是对任何HPV变体的第一次全基因组分析。本提案的具体目标是将欧洲HPV16变异体与两个非洲HPV16变异体组（非洲1型和非洲2型）和亚裔美国人变异体组进行比较。中心假设是，种族相关的变异在感染性和致癌性方面存在机械差异，并且这些差异在与变异相关的种族背景的个体的上皮组织中尤其严重。我们将在三个具体目标下进行这些研究：具体目标1：调查种族特异性HPV 16变异体致癌倾向的差异。具体目的2：比较HPV16变体种族特异性角质形成细胞的感染性。具体目标3：确定HPV16变异体种族特异性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.