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

项目摘要 尽管有抗逆转录病毒治疗，艾滋病毒感染者（PLWH）获得口腔HPV的风险增加， 与未感染组相比，最终发生HPV相关的口腔和口咽癌。而 目前正在努力了解高危成人人群HPV的流行病学，HPV感染的自然史， 儿童和青少年的口腔HPV在很大程度上未被研究。确定口腔HPV的自然史 儿童和青少年感染对于减少长期风险和有针对性地进行疫苗干预至关重要 程序.此外，PLWH中口腔HPV感染持续存在的机制尚不清楚， 但对预防HPV相关的癌症和疾病至关重要。关于艾滋病毒感染对儿童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丰度差异 孩子然而，对于可以促进微生物生长的关键微生物功能途径的了解有限。 口腔HPV感染该项目的总体目标是调查口腔HPV感染的自然史 并确定口腔微生物组在HPV持久性中的分类和功能作用， 围产期HIV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/青少年之间的差异。的 拟议的前瞻性观察研究将招募三组儿童及其各自的母亲， 尼日利亚。即：1）艾滋病毒感染者（HI），2）艾滋病毒接触者和未感染者（HEU），3）艾滋病毒未接触者和未感染者（HEU）。 未感染（HUU）儿童。核心假设是，HI和HEU儿童与HUU儿童相比， 口腔HPV类型特异性持久性的比率较高，这与独特的微生物群落有关 和功能途径。我们将通过三个具体目标来检验这一假设：1）表征和比较 HIV感染妇女和未感染妇女所生青年口腔HPV感染的自然史; 2）确定 感染HIV的儿童口腔HPV持续存在相关的炎症介导的功能途径; 以及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持久性的方法。对于第一个目标，将使用来自儿童-母亲对的口腔冲洗液样本 描述2年随访期间口腔HPV亚型分布的动态特征。第二个目标涉及 使用全基因组（鸟枪测序）对口腔微生物组进行功能表征，以研究其 与HPV类型特异性持久性的关系。对于第三个目标，我们将根据以下内容训练神经网络： 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 预测口腔HPV。该项目将导致更全面地了解受损的免疫状态 增加口腔HPV感染易感性和持久性。关于以下方面贡献的知识 口腔微生物群，将为未来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.