HIV, ART and the Intestinal Microbiota

描述(申请人提供)：持久抑制HIV病毒活性和恢复免疫功能是抗逆转录病毒治疗(ART)的主要目标，营养状况和肠道粘膜完整性可能会影响这些目标。一个“健康的”肠道微生物群既能促进营养状态，又能保持肠道完整性。然而，艾滋病毒感染、营养不良和饮食摄入改变可能会对肠道微生物区系产生不利影响，导致肠道完整性改变，并可能增加肠道细菌或其产品进入体循环的移位。我们小组正在泰米尔纳德邦农村地区对艾滋病毒感染者在开始抗逆转录病毒治疗前后的肠道粘膜完整性(由乳果糖：甘露醇渗透性确定)进行了一项研究，那里的艾滋病毒流行率是印度最高的。基于这一建议，我们将研究肠道微生物区系的变化在营养状态、免疫和病毒学状态、细菌易位和全身炎症中所起的作用，以及这些变化对抗逆转录病毒治疗的启动有何反应。这项研究将在这项家长研究中的两组艾滋病毒感染者中进行，一组是正常的，另一组是肠道通透性增加的。总体假设是，艾滋病毒感染和肠道通透性障碍将与肠道微生物区系谱相关联，与来自同一社区的类似年龄和性别的艾滋病毒阴性受试者相比，肠道微生物区系的分布更不健康，即不那么丰富和多样化。我们推测，“不太健康”的肠道微生物区系将与更大的炎症负担相关。识别这些差异将使我们能够进一步了解艾滋病毒炎症的发病机制，并使我们能够开发和测试有针对性的干预措施，例如使用益生菌或益生菌或饮食干预措施，这些干预措施可能会促进肠道微生物区系的恢复，并导致肠道完整性的有益变化和营养状况的改善。这项建议的具体目的是：1.阐明在抗逆转录病毒疗法开始之前，肠道通透性正常和增加的艾滋病毒感染患者的肠道微生物区系与免疫、病毒学和营养状况之间的关系，与来自同一社区、具有正常通透性的类似年龄和性别的非艾滋病毒感染对照相比。肠道微生物区系图谱(通过细菌16S rRNA焦磷酸测序确定)将通过丰度和多样性进行评估。来自每个样本的系统发育距离的主坐标分析(PCA)将被用来产生相关微生物群谱的集群，其将被查询以寻找与i)CD4计数、ii)病毒载量、iii)体重指数(BMI)、iv)上臂中围(MUAC)、v)细菌易位(血浆16S rRNA)和vi)全身炎症(血清hsCRP)以及2.在开始抗逆转录病毒治疗后6个月在HIV感染组和非HIV感染对照组中肠道微生物群谱的变化并确定i)CD4计数、ii)病毒载量、iii)BMI、Iv)MUAC，v)血浆16S rRNA水平和vi)hsCRP水平。

DESCRIPTION (provided by applicant): Durable suppression of HIV viral activity and the restoration of immune function are the primary goals of anti-retroviral therapy (ART), nutritional status and intestinal mucosal integrity may have an impact on these goals. A "healthy" intestinal microbiota both promotes nutritional status and preserves intestinal integrity. However, HIV infection, malnutrition, and altered dietary intake may adversely affect the intestinal microbiota, resulting in altered intestinal integrity and potentially, an increase in translocation of intestinal bacteria or their products into the systemic circulation. Our group is conducting a study of intestinal mucosal integrity (determined by lactulose:mannitol permeability) in HIV-infected individuals before and after they initiate ART, in rural Tamil Nadu, where rates of HIV prevalence are the highest in India. Based on this proposal, we will examine the role that alterations in the intestinal microbiota play in nutritional status, immune and virologic status, bacterial translocation and systemic inflammation and how these alterations respond to the initiation of ART. The study will be performed in two subgroups of HIV infected individuals from this parent study, one with normal and one with increased intestinal permeability, The overall hypothesis is that HIV infection and disruption of intestinal permeability will be associated with an intestinal microbiota profile which is "less healthy", i.e. less abundant and diverse, than that in HIV negative subjects of similar age and gender from the same community. We postulate that the "less healthy" intestinal microbiota will be associated with a greater inflammatory burden. Identification of these differences will allow us to further understand the pathogenesis of inflammation in HIV and allow us to develop and test targeted interventions, such as the use of pro- or pre-biotics or dietary interventions that may promote restoration of the profile of the intestinal microbiota and result in beneficial changes in intestinal integrity and improved nutritional status. The specific aims of this proposal are to: 1. Elucidate the associations between the intestinal microbiota profile and immune, virologic and nutritional status in HIV-infected patients with normal and increased intestinal permeability, immediately prior to the initiation of ART, compared to that of non-HIV-infected controls of similar age and gender from the same community with normal permeability. Intestinal microbiota profiles (determined by pyrosequencing of bacterial 16s rRNA) will be assessed by abundance and diversity. Principal co-ordinates analysis (PCA) of the phylogenetic distances from each sample will be used to generate clusters of related microbiota profiles, which will be queried for association with i) CD4 count, ii) viral load, iii) body mass index (BMI), iv) mid-upper arm circumference (MUAC), v) bacterial translocation (plasma 16S rRNA) and vi) systemic inflammation (serum hsCRP) and 2. to investigate changes in the intestinal microbiota profile 6 months after the initiation of ART in both HIV infected groups and the non-HIV infected controls and determine the associated changes in i) CD4 count, ii) viral load, iii) BMI, iv) MUAC, v) plasma 16S rRNA levels and vi) hsCRP levels.