The role of the enteric microbiome in chronic HIV pathogenesis and cardiovascular disease in HIV-infected individuals

项目摘要/摘要 即使接受抗逆转录病毒治疗，人类免疫缺陷病毒(HIV)感染者仍有更大的 死亡率高于未感染的人，主要死于炎症相关的非传染性疾病 疾病(NCD)，如心血管疾病(CVD)和肾功能障碍。这一慢性疾病的驱动因素 免疫激活和相关的CVD在很大程度上仍不清楚。最近的研究表明，有可能 肠道微生物群落中与艾滋病毒相关的重大干扰，这对人类健康至关重要 并参与许多代谢和免疫相互作用。我们来自撒哈拉以南非洲地区的初步数据 承受着艾滋病毒和相关心血管疾病巨大负担的人群表明，在这方面有明显的转变 微生物群落，这些与增加的全身炎症措施相对应。独立的 肠道微生物群落的变化已被证明会产生炎性代谢产物， 导致巨噬细胞和血小板活化、血栓形成和动脉斑块形成。我们建议研究 撒哈拉以南非洲人群中HIV相关肠道微生物的变化和系统免疫的测量 与这些变化相关的激活和心血管结果。然后我们将在体外和体内使用 研究HIV相关肠道微生物群落变化之间因果关系的模型 和心血管疾病。为了实现这一目标，我们将把肠道细胞模型暴露于感兴趣的艾滋病毒相关微生物和 测量对这些生物体的炎症反应。我们还将移植小鼠模型 大便微生物群落与动脉粥样硬化的关系，然后量化这些微生物引起的心血管疾病的发展 社区。我们希望这项工作将确定肠道微生物群落可能通过的机制 促进慢性HIV的心血管疾病发病，并为治疗干预提供机会 延长艾滋病毒感染者的寿命，提高他们的生活质量。

Project Summary/Abstract Even with antiretroviral therapy, Human Immunodeficiency Virus (HIV)-infected individuals still have a greater mortality than uninfected individuals, mostly due to death from inflammation-related non-communicable diseases (NCD), such as cardiovascular disease (CVD) and kidney dysfunction. The drivers of this chronic immune activation and associated CVD remain largely unknown. Recent studies have shown that there might be significant HIV-associated disruptions in the gut microbial community, which is essential to human health and is involved in many metabolic and immune interactions. Our preliminary data from Sub-Saharan African populations, which bear a great burden of HIV and associated CVD, suggest that there are clear shifts in this microbial community and that these correspond to increased measures of systemic inflammation. Independent of HIV, changes in the gut microbial community have been shown to produce inflammatory metabolites that cause macrophage and platelet activation, thrombosis, and arterial plaque formation. We propose to study HIV-associated gut microbial changes in Sub-Saharan African populations and measure systemic immune activation and cardiovascular outcomes associated with these changes. We will then use in vitro and in vivo models to investigate the causative relationship between HIV-associated gut microbial community changes and CVD. To accomplish this goal, we will expose gut cell models to HIV-associated microbes of interest and measure the inflammatory response to these organisms. We will also transplant mouse models of atherosclerosis with stool microbial communities and then quantify the development of CVD induced by these communities. It is our hope that this work will identify mechanisms by which the gut microbial community might contribute to CVD pathogenesis in chronic HIV and provide opportunities for therapeutic interventions to extend lifespan and improve quality of life for HIV-infected individuals.