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: 10440387
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440387
• 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.

艾滋病毒（+）女性患有宫颈预科剂和癌症以及人类乳头状病毒感染的高风险 （HPV），宫颈预科/癌症的病毒原因。遗传/表观遗传学方法的最新进展提供了 以前无法实现研究HPV病毒因素和其他当地感染影响的机会 HPV的自然历史和艾滋病毒（+）女性宫颈疾病的发展。在此提案下，我们将使用 下一代（下一代）测序进行精确的HPV基因组分析可以确定 在两个或多个时间点检测到的给定的HPV类型是否与其他不同的病毒感染相同 相同类型的HPV。这些数据将用于全面研究：HPV的特定类型差异 持久性及其与卓越者的关系； HPV重新激活的发生以及重新激活的频率 HPV持续存在并导致前锋。免疫状态对HPV自然中每个步骤的影响 历史。如果宫颈HPV可以重新激活并发展为预科剂，则将排除筛查年龄的停止 65年（在一般人群中完成）。此外，HPV DNA甲基化将是研究的 发现在HPV L1/L2区域中的甲基化与预科/癌症非常密切，而PILOT数据 提示HIV（+）女性可能存在甲基化和预科剂之间的类似关联。这项研究 因此，将提供有关与宫颈疾病发展相关的表观遗传修饰的见解， 并且可能被用来提高HPV测试的特异性和积极预测价值。重要的是， 子宫颈阴道微生物组可能会影响HPV自然史和HPV DNA甲基化，并且 也将研究。我们组的一项试点研究显示，HPV患病率降低，相对丰度较高 乳酸乳杆菌，但没有其他Lacobacillus物种，并过渡到Crispatus Community State 类型与减少的HPV相关。克里斯帕图斯乳杆菌的结果尤其有希望，因为 即使CD4低也观察到保护作用。但是，微生物群和HPV关系需要 在适当设计的艾滋病毒（+）队列研究中对任何未来的益生菌之前进行了适当的研究 可以考虑干预研究。目前几乎没有关于微生物群对影响的数据 HPV自然历史/进步（AIM 1建立）。我们还将研究菌群和HPV甲基化 （在AIM 2上建立），因为显示局部微生物群会改变邻近组织中的甲基化。总体而言，这些 综合研究涉及HPV自然历史/进步的关键方面，对 预防癌症。这项研究将利用来自WIHS（最大，最长的WIH）的中心收集的标本 HIV（+）（n = 2793）和高风险HIV（ - ）（n = 975）女性的术语队列。具体目的是在艾滋病毒（+）中 妇女研究：（i）使用下一代的重新激活在HPV自然历史和预科师风险中的作用 “精度” HPV基因组测定； （ii）HPV DNA甲基化及其与精确风险的关系；这 微生物组对HPV自然史，HPV甲基化和HPV进展的影响。