Factors mediating gut microbiota dysbiosis and metabolic disease in HIV patients

描述（由申请人提供）：由于HIV病毒直接靶向并大量消耗肠道CD 4 + T细胞，因此HIV感染为研究适应性免疫在塑造人类肠道定植微生物（微生物群）组成中的作用提供了独特的机会。与适应性免疫在决定哪些细菌将成功定植方面起着核心作用的观点一致，我们和其他人发现，艾滋病毒感染者的肠道微生物群组成发生了深刻的变化，并且具有高度的特征。微生物群失衡（生态失调）与代谢疾病有关，HIV感染者通常有代谢异常，包括高脂血症、低高密度脂蛋白胆固醇和胰岛素抵抗。抗逆转录病毒治疗（ART）药物与这些异常和脂肪营养不良（LD;面部、四肢和臀部脂肪萎缩，伴或不伴内脏脂肪堆积）相关。然而，并不是所有接受抗逆转录病毒治疗的人都会患病，其他致病因素也没有得到很好的理解。我们观察到肠道微生物群通常不能恢复到长期ART的健康美国成年人的典型状态，这表明有可能导致ART相关疾病的病理学。在这项资助的具体目标（SA）1中，我们将使用来自HIV阳性受试者的粪便和直肠乙状结肠活检样本的高通量测序，这些受试者有和没有LD和ART，以确定患有代谢疾病的个体是否更有可能患有HIV相关的生态失调和肠道炎症。SA 2和SA 3的目标是超越建立肠道微生物群与HIV感染中代谢疾病之间的关联，以了解潜在的机制。我们将解决的中心问题是1）为什么艾滋病毒感染会导致我们观察到的特定微生物群组成的变化？2)这些成分变化驱动代谢性疾病的机制是什么？3)具体涉及哪些分子因素？为了做到这一点，我们将探索不同的细菌物种的属性，在相对丰度与艾滋病毒感染和LD，无论是通过识别基因/操纵子，选择在他们的基因组（SA 2），并通过实验测定其免疫调节特性（SA 3）。我们的初步数据表明，有益的“共生”细菌，依赖于诱导FoxP 3 + CD 4 + T调节细胞（T细胞）的持久性优先丢失与艾滋病毒感染。我们假设 这可能反过来导致促炎细菌的生长、慢性炎症和代谢疾病的发展。因此，我们期望发现，HIV感染和/或LD耗尽的物种将更可能刺激Treg，并且将更可能在其基因组中具有已知的Treg诱导分子因子。相反，我们预计HIV和LD相关物种将刺激相对高水平的促炎细胞因子，并在其基因组中选择毒力相关因子。这项工作将确定肠道中细菌驱动因子/炎症抑制因子的获得/丧失是否会导致HIV感染者的代谢疾病。

DESCRIPTION (provided by applicant): Since the HIV virus directly targets and substantially depletes gut CD4+ T cells, HIV infection provides a unique opportunity to study the role of adaptive immunity in shaping the composition of microbes that colonize the gut (the microbiota) in humans. Consistent with the notion that adaptive immunity plays a central role in determining which bacteria will successfully colonize, we and others have found that HIV-infected individuals have profoundly altered and highly characteristic gut microbiota composition. Microbiota inbalance (dysbiosis) has been associated with metabolic disease, and HIV-infected individuals often have metabolic abnormalities including hypertriglyceridemia, low high-density lipoprotein cholesterol, and insulin resistance. Antiretroviral therapy (ART) drugs are associated with these abnormalities and with lipodystrophy (LD; lipoatrophy in the face, extremities and buttocks with or without visceral fat accumulation). However not everyone on ART develops disease and other contributing factors are not well understood. We observed that gut microbiota is often not restored to a state typical of healthy US adults with long-term ART, indicating a potential to contribute to the pathology of ART-linked diseases. In Specific Aim (SA)1 of this grant, we will use high-throughput sequencing of fecal and rectosigmoid biopsy samples from HIV-positive subjects with and without LD and ART to determine whether individuals with metabolic disease will more likely have HIV-associated dysbiosis and gut inflammation. The goal of SA2 and SA3 is to go beyond the establishment of an association between gut microbiota and metabolic disease in HIV infection to understand underlying mechanisms. Central questions that we will address are 1) Why does HIV infection lead to the specific microbiota compositional changes that we observe? 2) What is the mechanism by which these compositional changes may drive metabolic disease? 3) What specific molecular factors are involved? To do this we will explore the properties of bacterial species that differ in relative abundance with HIV infection and LD, both by identifying genes/operons that are selected for in their genomes (SA2), and by experimental determination of their immune-modulatory properties (SA3). Our preliminary data suggest that beneficial "symbiotic" bacteria that depend on the induction of FoxP3+ CD4+ T regulatory cells (Tregs) for persistence are preferentially lost with HIV infection. We hypothesize that this may in turn lead to the outgrowth of pro-inflammatory bacteria, chronic inflammation and the development of metabolic disease. Thus, we expect to find that species depleted with HIV infection and/or LD will more likely stimulate Tregs and will more likely have known Treg inducing molecular factors in their genomes. Conversely we expect that HIV and LD-associated species will stimulate relatively high levels of pro-inflammatory cytokines and will have a selection for virulence-associated factors in their genomes. This work will establish whether gain/loss of bacterial drivers/suppressors of inflammation in the gut contributes to metabolic disease in HIV-infected individuals.