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

HIV()妇女患宫颈癌前病变和癌症以及感染人类乳头瘤病毒的风险很高 人乳头瘤病毒(HPV)，是导致宫颈癌前期/癌症的病毒原因。遗传/表观遗传学方法的最新进展提供了 以前无法获得的机会来研究HPV病毒因素和其他局部感染对 HIV()妇女HPV的自然病史和宫颈疾病的发展。在这项提议下，我们将使用 下一代(下一代)测序，以进行精确的HPV基因组分析，能够确定 在两个或更多时间点检测到的特定HPV类型是相同的病毒感染还是不同的病毒感染 同类型的人乳头瘤病毒。这些数据将被用来全面研究：HPV的特定类型差异 持续性及其与癌前病变的关系；HPV复活的发生和复活频率 HPV持续存在并导致癌前病变；免疫状态对HPV中每一个步骤的影响是自然的 历史。如果宫颈HPV可以重新激活并进展为癌前病变，将排除年龄停止筛查的可能性。 65岁(这在普通人群中是这样的)。此外，还将研究HPV DNA甲基化，因为我们 发现HPV L1/L2区域的甲基化与癌前病变/癌症密切相关，以及试点数据 提示甲基化和癌前病变之间的相似关联可能存在于HIV()女性身上。这项研究 因此将为与宫颈疾病的发展相关的表观遗传修饰提供洞察， 可用于提高HPV检测的特异性和阳性预测值。重要的是 宫颈阴道微生物群可能同时影响HPV的自然病史和HPV DNA甲基化以及 也将进行研究。我们小组的一项初步研究表明，相对丰度高的人乳头瘤病毒感染率较低。 而不是其他种类的乳杆菌，并过渡到卷曲乳杆菌群落状态 类型与减少事件HPV有关。卷叶乳杆菌的结果尤其令人振奋，因为 即使在低CD4的情况下也能观察到保护作用。然而，微生物区系和HPV之间的关系需要 在未来任何益生菌之前，在适当设计的HIV()队列研究中进行足够大的研究 可以考虑进行干预性研究。目前几乎没有关于微生物区系对 人乳头瘤病毒自然发展史/进展(以目标1为基础)。我们还将研究微生物区系和人乳头瘤病毒甲基化。 (以AIM 2为基础)，因为局部微生物区系被证明改变了邻近组织的甲基化。总的来说，这些 综合研究涉及HPV自然历史/进展的关键方面，具有重大意义 癌症预防。这项研究将利用每半年从WIHS收集的样本，最大的，长的 HIV()(N=2793)和高危HIV(-)(N=975)妇女的足月队列。具体目标是，在艾滋病毒() 女性，研究：(I)重新激活在HPV自然病史和癌症前风险中的作用，使用下一代 “精密”HPV基因组分析；(Ii)HPV DNA甲基化及其与癌前风险的关系； 微生物组对HPV自然历史、HPV甲基化和HPV进展的影响。

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.