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

项目摘要 微生物群失衡通过改变宿主免疫功能影响癌症的发展和治疗结果 反应和炎症。卡波西肉瘤（KS）是艾滋病病毒感染者最常见的癌症 卡波西肉瘤相关疱疹病毒（KSHV）感染。尽管有抗逆转录病毒治疗，KS仍然 在艾滋病患者中很常见。目前尚不清楚哪些因素可能影响发展， AIDS-KS的治疗结果？针对RFA-CA-22-056，标题为：“基础/转化研究 艾滋病毒感染者（PLWH）和癌症患者中代表性不足的健康差异”，该申请特别 解决了非洲人口服务不足的问题，这些人口长期以来有大量新的艾滋病毒感染， 本项研究的目的是阐明艾滋病相关KS（AIDS-KS）的发病机制，并确定有效的治疗方法， 靶点和试剂以及预后生物标志物。我们最近已经表明， 口腔AIDS-KS中的微生物多样性和特定微生物群的富集，并证明细菌和 其产物脂多糖和鞭毛蛋白通过增强炎症促进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，特定的微生物群调节 炎症影响AIDS-KS患者KS发展和治疗结果。我们有 组建了一个强大的合作团队，在HIV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， HIV感染者和AIDS-KS人群由本项目的研究人员指导。我们将确定 通过在初治患者中进行病例对照分析，研究特定微生物群对炎症和AIDS-KS发展的影响 AIDS-KS和没有KS的HIV/KSHV患者（目标1）;并检查特定微生物群对 通过对接受抗逆转录病毒治疗的AIDS-KS患者的病例对照纵向分析，探讨KS的治疗结局 治疗，然后在独立队列中进行验证分析（目标2）。这一跨学科项目将 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， AIDS-KS患者使用先进的机器学习方法。我们希望找出影响 AIDS-KS患者的发展和治疗结果。这项工作意义重大，将 对AIDS-KS患者的预后、预防和治疗有重要影响。这将是第一次， 将在来自良好表征的队列的AIDS-KS患者中系统地检查微生物群的数量。拟议 创新的方法，如空间单细胞测序和机器学习，将产生独特的， 前所未有的结果，提供了新的见解的发病机制和治疗结果的艾滋病-KS。

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.