HPV, HIV and Oral Microbiota Interplay in Nigerian Youth (HOMINY)

项目总结 尽管接受抗逆转录病毒治疗，但艾滋病毒携带者(PLWH)感染口服HPV和 与未感染组相比，最终发展为HPV相关的口腔和口咽癌。而当 正在努力了解HPV高危成人人群的流行病学， 儿童和青少年中的口腔HPV在很大程度上没有得到调查。口腔人乳头瘤病毒自然病史的判定 儿童期和青春期的感染在降低长期风险和针对性疫苗干预方面至关重要 程序。此外，口腔HPV感染在PLWH中持续存在的机制尚不清楚。 但对预防HPV相关癌症和疾病至关重要。关于艾滋病毒感染对人类健康影响的最新研究 与HIV+和HIV-相比，口腔微生物组显示出某些细菌的丰度不同 孩子们。然而，对关键的微生物功能途径的了解有限，这可能有助于 口腔HPV感染。这项计划的总体目标是调查口腔HPV感染的自然病史。 并确定口腔微生物组在HPV持续存在中的分类和功能作用 围产期艾滋病毒暴露、感染和治疗。为了实现这一目标，我们将利用一个独特的 感染艾滋病毒的母亲所生的儿童/青少年与未感染艾滋病毒的母亲所生的儿童/青少年的大队列。这个 拟议的前瞻性观察研究将在#年招募三组儿童及其各自的母亲 尼日利亚。即：1)艾滋病毒感染(HI)，2)艾滋病毒暴露和未感染(HEU)和3)艾滋病毒未暴露和- 未感染(HUU)儿童。中心假设是，与HUU儿童相比，HI和HEU儿童将 有较高的口腔HPV型特异性持久率，这与独特的微生物群落有关 和功能通路。我们将通过三个具体目标来检验这一假设：1)描述和比较 感染艾滋病毒妇女和未感染妇女所生青少年中口腔HPV感染的自然病史；2)确定 感染HIV的儿童中与口腔HPV持续相关的炎症介导的功能通路； 3)开发和测试基于临床和口腔分类/功能微生物组的深度学习算法 预测口腔HPV持久性的资料。对于第一个目的，将使用来自孩子-母亲配对的口腔漱口水样本 目的：研究口腔HPV亚型分布的动态变化规律。第二个目标涉及 用全基因组(鸟枪法测序)研究口腔微生物组的功能 与HPV类型特异性持久性的关系。对于第三个目标，我们将基于以下方面训练神经网络 纵向微生物组特征、细胞因子水平和其他风险因素，以确定哪些特征强烈 预测口腔HPV。这个项目将导致对免疫受损状态的更全面的了解 增加对口腔HPV感染的易感性和持久性。获得关于以下方面的贡献的知识 口腔微生物区系，将为今后的预防和治疗干预奠定基础。

PROJECT SUMMARY Despite antiretroviral therapy, people living with HIV (PLWH) have an increased risk of acquiring oral HPV and ultimately developing HPV-associated oral and oropharyngeal cancers compared to uninfected groups. While efforts are being made to understand the epidemiology of HPV-at-risk adult populations, the natural history of oral HPV in children and adolescents is largely uninvestigated. Determining the natural history of oral HPV infection in childhood and adolescence is critical in mitigating long-term risk and targeting vaccine intervention programs. Furthermore, the mechanisms underlying the persistence of oral HPV infection in PLWH are unclear, yet crucial to preventing HPV-associated cancers and diseases. Recent studies of the impact of HIV infection on the oral microbiome have shown differences in abundance of certain bacteria as compared HIV+ and HIV- children. Yet, there is limited understanding regarding the key microbial functional pathways that could facilitate oral HPV infection. The overall objectives of this project are to investigate the natural history of oral HPV infection and determine the taxonomic and functional roles of the oral microbiome in HPV persistence in the context of perinatal HIV exposure, infection, and treatment. To accomplish this, we will take advantage of a unique and large cohort of children/adolescents born to HIV-infected mothers vs. those born to HIV uninfected mothers. The proposed prospective observational study will recruit three groups of children and their respective mothers in Nigeria. Namely: 1) HIV-infected (HI), 2) HIV exposed-and-uninfected (HEU) and 3) HIV-unexposed-and- uninfected (HUU) children. The central hypothesis is that HI and HEU children, compared to HUU children, will have higher rates of oral HPV type-specific persistence, which is associated with a distinct microbial community and functional pathways. We will test this hypothesis via three specific aims: 1) Characterize and compare the natural history of oral HPV infection among youth born to HIV-infected women and uninfected women; 2) Identify inflammatory-mediated functional pathways associated with oral HPV persistence in children infected with HIV; and 3) Develop and test a deep learning algorithm based on clinical and oral taxonomic/functional microbiome profiles to predict oral HPV persistence. For the first aim, oral rinse samples from child-mother pairs will be used to characterize the dynamics of oral HPV subtype distribution over 2 years of follow-up. The second aim involves functional characterization of the oral microbiome using whole genome (shotgun sequencing) to investigate its relationship with HPV-type-specific persistence. For the third aim, we will train neural networks based on longitudinal microbiome features, cytokine levels, and other risk factors to determine which features strongly predict oral HPV. This project will lead to a more complete understanding of how impaired immunological states increase susceptibility to oral HPV infection and persistence. Knowledge gained regarding the contribution of oral microbiota, will lay a foundation for future prevention and therapeutic interventions.