Next Generation of HPV and Cervical Cancer Research in HIV+ Women

HIV 女性中的下一代 HPV 和宫颈癌研究

• 批准号: 10203871
• 负责人: Robert D Burk
• 金额: $ 65.58万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-11 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203871
• 关键词: Address; Affect; Age; Biological Assay; CD4 Lymphocyte Count; Centers for Disease Control and Prevention (U.S.); Cervical; Cervical Cancer Screening; Clinical; Cohort Studies; Communities; DNA Methylation; Data; Detection; Development; Disease; Epigenetic Process; Future; General Population; Genetic; Genomics; HIV; Human Development; Human Papillomavirus; Human papilloma virus infection; Infection; Intervention Studies; Lactobacillus; Lead; Longitudinal Studies; Longitudinal cohort; Longitudinal prospective study; Longterm Follow-up; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Methods; Methylation; Modification; Natural History; Oncogenic; Patient risk; Pilot Projects; Population; Predictive Value; Prevalence; Probiotics; Prospective Studies; Reporting; Research; Research Design; Risk; Risk Factors; Role; Screening for cancer; Site; Specificity; Specimen; Testing; Time; Tissues; United States National Institutes of Health; Viral; Virus Diseases; Woman; Women' s Interagency HIV Study; Women' s Role; anticancer research; cancer prevention; cervical cancer prevention; cervicovaginal; cervicovaginal microbiome; clinically relevant; cohort; design; high risk; immunological status; improved; insight; methylation pattern; microbiome; microbiota; next generation; next generation sequencing; protective effect; risk stratification; screening; screening guidelines; virus characteristic

HIV(+) women have high risk of cervical precancer and cancer as well as infection with human papillomavirus (HPV), the viral cause of cervical precancer/cancer. Recent advances in genetic/epigenetic methods provide previously unachievable opportunities to study the HPV viral factors and other local infectious influences on the natural history of HPV and development of cervical disease in HIV(+) women. Under this proposal, we will use next generation (next-gen) sequencing to conduct precision HPV genomic analysis able to determine whether a given HPV type detected at two or more time points is the same exact viral infection versus different HPVs of the same type. These data will be used to comprehensively study: type-specific differences in HPV persistence and their relation with precancer; the occurrence of HPV reactivation and how often reactivated HPV persists and leads to precancer; the impact of immune status on each of these steps in HPV natural history. If cervical HPV can reactivate and progress to precancer, it would preclude screening cessation at age 65 years (which is done in the general population). Furthermore, HPV DNA methylation will be studied, as we found methylation in the HPV L1/L2 region very strongly associated with precancer/cancer, and pilot data suggest similar associations between methylation and precancer may exist for HIV(+) women. This research therefore will provide insight into the epigenetic modifications related to the development of cervical disease, and could possibly be used to improve the specificity and positive predictive value of HPV testing. Importantly, the cervicovaginal microbiome may influence both the HPV natural history and HPV DNA methylation and will also be studied. A pilot study by our group showed reduced HPV prevalence with high relative abundance of Lactobacillus crispatus but not other Lacobacillus species, and transition to a L. crispatus community state type was associated with reduced incident HPV. The L. crispatus results were especially promising since the protective effects were observed even with low CD4. However, the microbiota and HPV relationship needs to be studied in appropriately designed HIV(+) cohort studies of adequate size before any future probiotic intervention studies may be considered. There are currently little data regarding the impact of the microbiota on HPV natural history/progression (building on Aim 1). We will also study the microbiota and HPV methylation (building on Aim 2), as local microbiota was shown to alter methylation in neighboring tissue. Overall, these integrated studies address critical aspects of HPV natural history/progression, with significant implications to cancer prevention. This study will utilize semiannually collected specimens from the WIHS, the largest, long term cohort of HIV(+) (N=2793) and high risk HIV(-) (N=975) women. The Specific Aims are, in HIV(+) women, to study: (i) The role of reactivation in HPV natural history and precancer risk, using next-gen “precision” HPV genomic assays; (ii) HPV DNA methylation and its relation with precancer risk; The microbiome's impact on HPV natural history, HPV methylation, and HPV progression.

HIV（+）女性患宫颈癌前病变和癌症以及感染人乳头瘤病毒的风险较高 (HPV)，宫颈癌前期/癌症的病毒原因。遗传/表观遗传方法的最新进展提供了 以前无法实现的机会来研究 HPV 病毒因素和其他局部感染对 HIV（+）女性的 HPV 自然史和宫颈疾病的发展。根据该提案，我们将使用 下一代（next-gen）测序进行精确的 HPV 基因组分析，能够确定 在两个或多个时间点检测到的特定 HPV 类型是否是相同的病毒感染或不同的病毒感染 相同类型的 HPV。这些数据将用于综合研究： HPV 类型特异性差异 持久性及其与癌前病变的关系； HPV 再激活的发生情况以及再激活的频率 HPV 持续存在并导致癌前病变；免疫状态对 HPV 自然感染中每个步骤的影响 历史。如果宫颈 HPV 可以重新激活并进展为癌前病变，那么就可以排除在年龄时停止筛查的可能性 65岁（这是在一般人群中进行的）。此外，我们还将研究 HPV DNA 甲基化 发现 HPV L1/L2 区域的甲基化与癌前/癌症密切相关，并且试验数据 研究表明，对于 HIV（+）女性来说，甲基化与癌前病变之间可能存在类似的关联。这项研究 因此将深入了解与宫颈疾病发展相关的表观遗传修饰， 并可能用于提高 HPV 检测的特异性和阳性预测值。重要的是， 宫颈阴道微生物组可能影响 HPV 自然史和 HPV DNA 甲基化， 也将被研究。我们小组的一项试点研究表明 HPV 患病率降低且相对丰度较高 卷曲乳杆菌而非其他乳杆菌物种，并转变为卷曲乳杆菌群落状态 类型与 HPV 发生率降低相关。卷曲卷曲乳杆菌的结果特别有希望，因为 即使 CD4 水平较低，也能观察到保护作用。然而，微生物群和 HPV 的关系需要 在任何未来的益生菌之前，在适当设计的、足够规模的 HIV(+) 队列研究中进行研究 可以考虑干预研究。目前关于微生物群对健康的影响的数据还很少。 HPV 自然史/进展（基于目标 1）。我们还将研究微生物群和 HPV 甲基化 （以目标 2 为基础），因为局部微生物群被证明可以改变邻近组织的甲基化。总体而言，这些 综合研究解决了 HPV 自然史/进展的关键方面，对 癌症预防。这项研究将利用从 WIHS 收集的半年样本，WIHS 是最大、最长的研究中心。 HIV(+) (N=2793) 和高危 HIV(-) (N=975) 女性足月队列。具体目标是，针对 HIV(+) 女性，使用下一代研究：(i) 再激活在 HPV 自然史和癌前风险中的作用 “精准”HPV 基因组检测； (ii) HPV DNA 甲基化及其与癌前风险的关系；这 微生物组对 HPV 自然史、HPV 甲基化和 HPV 进展的影响。