The enteric microbiome in treated and progressive HIV infection

描述(申请人提供)：人体肠道中有一个极其多样化的微生物群落，统称为“微生物群”。这种微生物群与人类共同进化了5亿年，以帮助关键的宿主代谢和免疫功能。微生物组的变化对糖尿病、肥胖症、炎症性肠病、癫痫和多发性硬化症等疾病状态的影响直到现在才被认识到。很明显，人类免疫缺陷病毒(HIV)感染对肠道粘膜环境有深远的影响，其特征之一是肠道相关淋巴组织(GALT)中的CD4T细胞迅速而严重地耗尽。尽管如此，关于HIV感染时肠道微生物区系发生的变化以及这些变化对宿主免疫和HIV疾病进展的潜在影响的信息很少。人们认为，艾滋病毒感染会导致肠道炎症和肠粘膜通透性增加，随后腔内微生物产物会转移到体循环中。这种微生物易位驱动慢性免疫激活，从而导致T细胞耗尽和艾滋病毒疾病的进展。HIV导致肠道上皮功能障碍和微生物易位的机制仍不完全清楚。关于肠道微生物种群如何影响这一过程或受到这一过程的影响，我们知道的更少。尽管如此，已有研究表明，在慢病毒介导的疾病感染早期，人类和非人类灵长类动物的肠道微生物区系可以发生显著变化。微生物区系异常与炎症性肠病的肠道炎症密切相关，有数据表明，肠道炎症在其中起因果作用。这表明，微生物群可能在调节肠道功能障碍中发挥直接作用。因此，必须更详细地了解肠道微生物群的变化对艾滋病毒相关的肠道功能障碍和疾病进展的影响。这项建议试图通过使用高通量下一代测序(NGS)来使用人类受试者的粪便、组织和血浆来全面调查肠道微生物种群的动态变化，以确定肠道微生物群和病毒体在HIV感染中的作用。我们将定义人类肠道微生物组在未感染状态下的新成分，以及在晚期艾滋病毒/艾滋病和开始抗逆转录病毒治疗时发生的变化(ART)。我们将把粪便中的微生物群与肠道组织相关的微生物物种联系起来，并探索组织相关微生物促进艾滋病毒疾病进展的机制。最后，我们将对肠道微生物群的变化促进艾滋病毒疾病进展的机制进行分析，以补充这些研究。这些研究将有助于更详细地从根本上了解肠道生态及其在艾滋病毒疾病进展中的作用之间的关系，并确定针对肠道微生物组的潜在新干预措施，以治疗艾滋病毒感染的长期炎症后果。

DESCRIPTION (provided by applicant): The human gut harbors an enormously diverse community of microorganisms collectively referred to as the "microbiome". This microbiome has co-evolved with humans over half a billion years to assist in critical host metabolic and immune function. The impact of changes in the microbiome on disease states as diverse as diabetes, obesity, inflammatory bowel disease, epilepsy, and multiple sclerosis is only now being recognized. It is clear that human immunodeficiency virus (HIV) infection has profound effects on the intestinal mucosal environment with one of the hallmarks of HIV infection being a rapid and profound depletion of CD4+ T cells within gut associated lymphoid tissue (GALT). Despite this, there is a paucity of information regarding the changes that occur in the intestinal microbiota in HIV infection and the potential effects of these changes on host immunity and HIV disease progression. It is believed that HIV infection results in intestinal inflammation and increased intestinal mucosal permeability with subsequent translocation of luminal microbial products into the systemic circulation. This microbial translocation drives chronic immune activation, which results in T cell exhaustion and HIV disease progression. The mechanism by which HIV induces intestinal epithelial dysfunction and microbial translocation remains incompletely understood. Even less is known about how gut microbial populations may influence, or be influenced by, this process. Still, it has been shown that enteric microbiota in humans and nonhuman primates can be significantly altered early in infection by lentiviral-mediated disease. Abnormal microbiota are strongly associated with intestinal inflammation in inflammatory bowel disorders with data suggesting a causal role in gut inflammation. This suggests that the microbiome may play a direct role in mediating intestinal dysfunction. It is therefore critical to develop a more detailed understanding of the impact of alterations in the intestinal microbiome on HIV-associated intestinal dysfunction and disease progression. This proposal seeks to define the role of the enteric microbiome and virome in HIV infection by using high-throughput next generation sequencing (NGS) to conduct a comprehensive survey of dynamic changes in gut microbial populations using stool, tissue and plasma from human subjects. We will define novel components of the human intestinal microbiome in the uninfected state as well as alterations that occur with advanced HIV/AIDS and upon initiation of antiretroviral therapy (ART). We will link the microbiome in stool with microbial species associated with the intestinal tissue and explore the mechanism by which tissue associated microbes contribute to HIV disease progression. Finally, we will compliment these studies with an analysis of the mechanism by which changes in the enteric microbiome contribute to HIV disease progression. These studies will result in a more detailed fundamental understanding of the relationship between the intestinal ecology and its role in HIV disease progression and also identify potential new interventions targeting the intestinal microbiome to treat the long term inflammatory consequences of HIV infection.