The enteric microbiome in HIV-associated chronic immune activation and cardiovascular disease

项目摘要 尽管抗逆转录病毒疗法（ART）取得了成功，但感染人类免疫缺陷病毒的个体 (HIV)仍然比未感染的人有更高的死亡率，主要是由于炎症死亡- 这些疾病与非传染性疾病（NCD）相关，如心血管疾病（CVD）和肾功能障碍。 这种慢性免疫激活和相关CVD的驱动因素在很大程度上仍然未知。最近的研究 已经表明，HIV感染导致肠道微生物群落的破坏，这些改变是 与肠道屏障功能障碍、细菌移位和全身免疫激活相关。然而，在这方面， 已发表的研究主要研究发达国家的人口，尽管最大的 发展中国家存在HIV感染和相关CVD的负担。我们是唯一一个 关于生活在撒哈拉以南非洲地区的人群中肠道微生物组中与艾滋病毒相关的变化。我们的出版 研究和初步数据表明，肠道微生物组，包括细菌和病毒， 与HIV感染有关，并且这些对应于全身炎症的增加。独立于 肠道微生物群落的变化已被证明会产生炎症代谢物， 引起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 两个撒哈拉以南非洲人群中HIV相关的肠道微生物变化并测量全身免疫 与这些变化相关的激活和心血管结局。这些研究将确定微生物 候选人，我们将在体外和体内模型中使用，以研究之间的因果关系 HIV相关的肠道微生物群落变化和CVD我们会让肠道和血管细胞接触艾滋病毒- 相关的感兴趣的微生物，并测量对这些生物体的炎症反应。我们还将使用 将候选微生物和/或粪便群落移植到已建立的动脉粥样硬化鼠模型中， 动物来表征这些微生物诱导的心血管疾病的发展。该项目的具体目标 目的是：1）确定肠道微生物群落的变化、免疫增强 激活和心血管疾病的艾滋病毒感染者在撒哈拉以南非洲和2） 两者都用在 体外和体内模型，以评估HIV相关肠道微生物群落 促进慢性炎症和心血管疾病。 拟议工作的目标是确定具体的 肠道微生物组（包括细菌、病毒、真菌和 寄生虫）有助于慢性HIV感染的CVD发病机制，并有助于告知新的 利用肠道微生物组延长寿命和改善生活质量的治疗干预措施 艾滋病毒感染者。

Project Summary Despite the success of antiretroviral therapy (ART), individuals infected with Human Immunodeficiency Virus (HIV) still have a greater mortality than those who are uninfected, mostly due to death from inflammation- related non-communicable diseases (NCDs), 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 HIV infection results in disruptions in the gut microbial community and these alterations are associated with gut barrier dysfunction, bacterial translocation, and systemic immune activation. However, published studies have primarily examined populations in the developed world, even though the greatest burden of HIV-infection and associated CVD exists in the developing world. We remain the only group to report on HIV-associated changes in the gut microbiome in populations living in sub-Saharan Africa. Our published studies and preliminary data indicate that there are clear shifts in the gut microbiome, both bacterial and viral, with HIV-infection 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 two sub-Saharan African populations and measure systemic immune activation and cardiovascular outcomes associated with these changes. These studies will identify microbial candidates that we will then use in in vitro and in vivo models to investigate the causative relationship between HIV-associated gut microbial community changes and CVD. We will expose gut and vascular cells to HIV- associated microbes of interest and measure the inflammatory response to these organisms. We will also use an established murine model of atherosclerosis to transplant candidate microbes and/or stool communities into animals to characterize the development of CVD induced by these microbes. The specific aims of this project are to: 1) Determine the associations between changes in enteric microbial communities, increased immune activation, and cardiovascular disease in HIV-infected individuals in sub-Saharan Africa and 2) Utilize both in vitro and in vivo models to assess mechanisms by which HIV-associated enteric microbial communities promote chronic inflammation and cardiovascular disease. The goal of the proposed work is to identify specific mechanisms by which HIV-associated alterations in the gut microbiome (including bacteria, viruses, fungi and parasites) contribute to CVD pathogenesis in chronic HIV infection and help inform the development of new therapeutic interventions that leverage the gut microbiome to extend lifespan and improve quality of life for HIV-infected individuals.