Impact of microbiota on AIDS-Kaposi’s sarcoma development and therapy

项目摘要 微生物区系失衡通过改变宿主免疫影响癌症的发展和治疗结果 反应和炎症。卡波西肉瘤(KS)是人类免疫缺陷病毒感染患者最常见的致癌原因 感染卡波西肉瘤相关疱疹病毒(KSHV)。尽管接受了抗逆转录病毒治疗，KS仍然 在感染艾滋病毒的患者中很常见。目前尚不清楚哪些因素可能会影响发展和 艾滋病的治疗结果--KS？对RFA-CA-22-056号文件的答复： 代表不足的艾滋病毒(PLWH)和癌症患者的健康差距“，这项申请特别 解决服务不足的非洲人口，这些人新感染艾滋病毒的人数很多，长期- 学期目标是描述艾滋病相关KS(AIDS-KS)的发病机制，并找到有效的治疗方法 靶标和制剂以及预测生物标记物。我们最近展示了口腔的贫乏 口腔AIDS-KS中微生物多样性和特定微生物区系的富集性，并证明细菌和 其产物脂多糖和鞭毛蛋白通过促进炎症促进KSHV诱导的肿瘤发生 在临床前KSHV诱导的KS动物模型中。我们的假设是，特定的微生物区系调节 炎症对艾滋病-KS患者KS发展和治疗结果的影响。我们有 组建了一支强大的协作团队，在艾滋病毒感染、KSHV生物学、微生物组、临床 科学、流行病学、统计学、计算生物学和机器学习。我们将利用 在非洲进行的长期临床研究，具有明确的横断面、病例对照和纵向队列 由该项目的调查人员指导的艾滋病毒感染者和艾滋病-KS人群。我们将确定 用朴素的病例对照分析研究炎症和AIDS-KS发展的特定微生物区系 艾滋病-KS和没有KS的HIV/KSHV患者(目标1)；并检查特定微生物区系对 艾滋病-KS患者抗逆转录病毒治疗的病例对照纵向分析 治疗后在独立队列中进行验证分析(目标2)。这个跨学科的项目将 分析分子、病毒学、微生物、免疫学、单细胞空间组学和临床特征 艾滋病-KS患者使用先进的机器学习方法。我们希望找出影响经济增长的因素 艾滋病-KS患者的发展和治疗结果。拟议的工作意义重大，并将 对艾滋病-KS患者的预后、预防和治疗产生影响。这将是第一次扮演这个角色 将对来自具有良好特征的队列的艾滋病-KS患者进行系统的微生物区系检查。建议数 空间单细胞测序和机器学习等创新方法将产生独特的和 史无前例的结果，为艾滋病-KS的发病机制和治疗结果提供了新的见解。

Project Abstract Microbiota imbalance impacts the development and therapeutic outcome of cancer by altering host immune response and inflammation. Kaposi’s sarcoma (KS) is the most common cancer in HIV-infected patients caused by infection of Kaposi’s sarcoma-associated herpesvirus (KSHV). Despite antiretroviral therapy, KS remains common among HIV-infected patients. It remains unclear what factors might influence the development and therapeutic outcome of AIDS-KS? In response to RFA-CA-22-056 entitled: “Basic/Translational Research on Health Disparities in Underrepresented People Living with HIV (PLWH) and Cancer”, this application specifically addresses the underserved African populations that have high numbers of new HIV infections with the long- term goal is to delineate the pathogenesis of AIDS-associated KS (AIDS-KS), and identify effective therapeutic targets and agents as well as prognostic biomarkers. We have recently shown the impoverishment of oral microbial diversity and enrichment of specific microbiota in oral AIDS-KS, and demonstrated that bacteria and their products lipopolysaccharide and flagellin promote KSHV-induced tumorigenesis by enhancing inflammation in a preclinical KSHV-induced KS animal model. Our hypothesis is that specific microbiota regulates inflammation to impact KS development and therapeutic outcome in AIDS-KS patients. We have assembled a strong collaborative team with diverse expertise in HIV infection, KSHV biology, microbiome, clinical sciences, epidemiology, statistics, computational biology and machine learning. We will take advantage of the long-term clinical studies in Africa with well-defined cross-sectional, case-control and longitudinal cohorts of large HIV-infected and AIDS-KS populations directed by investigators of this project. We will determine the impact of specific microbiota on inflammation and AIDS-KS development by performing case-control analyses in naïve AIDS-KS and HIV/KSHV patients without KS (Aim 1); and examine the impact of specific microbiota on the therapeutic outcome of KS by case-control longitudinal analyses of AIDS-KS patients undergoing anti-retroviral therapy followed by validation analyses in an independent cohort (Aim 2). This interdisciplinary project will analyze the molecular, virological, microbial, immunological, single cell spatial omics, and clinical features of AIDS-KS patients using advanced machine learning approaches. We expect to identify factors that influence the development and therapeutic outcome of AIDS-KS patients. The proposed work is highly significant, and will have prognostic, preventive and therapeutic impacts on AIDS-KS patients. This will be the first time that the role of microbiota will be systematically examined in AIDS-KS patients from well-characterized cohorts. The proposed innovative approaches such as spatial single cell sequencing and machine learning will generate unique and unprecedented results, providing novel insights into the pathogenesis and therapeutic outcome of AIDS-KS.