Alterations in Lung Microbiome in Acute and Chronic HIV infection

描述(申请人提供)：肺部已被认为是人类免疫缺陷病毒1型(HIV-1)感染的感染性和非感染性并发症的主要目标之一。尽管HAART已经启动，但H1V-1/AIDS的肺部并发症仍然是HIV-1感染患者发病和死亡的主要原因。先天和获得性免疫反应的缺陷增加了由HIV-1感染者中的病原体和机会性微生物引起的肺炎的风险。肺炎后，这些人会经历肺功能的下降，这在未感染HIV-1的人群中没有观察到。目前尚不清楚在HIV-1感染背景下肺功能的恶化或慢性肺部疾病的发展是否与免疫缺陷、肺微生物群的改变以及随后的慢性肺部炎症的发展有关。通过我们资助的“HIV相关肺部感染和并发症的纵向研究”项目，我们利用高通量测序平台启动了对肺部和外周的nef序列进化的系统分析。这些研究揭示了HLV-1nef变异的有趣模式，这些变异与HIV-1相关的肺动脉高压有关，这是慢性HIV-1的一种非传染性并发症。随着更先进的高通量测序技术的出现，我们可以产生足够高质量和深度的数据集，使我们能够推断疾病阶段的变化如何影响肺部微生物区系，并影响与HIV-1相关的急性和慢性肺部并发症的发展和进展。利用科罗拉多大学目前在艾滋病毒-1致病机制、肺部免疫学、计算生物学和生物信息学领域的丰富专业知识，我们假设与L-ILV-1感染相关的免疫缺陷会导致肺微生物群的扩大，以及对微生物区系和艾滋病毒-1变异株的炎症反应将导致非传染性慢性肺部并发症，如肺动脉高压。在具体目标1中，我们将确定与血清阴性的健康对照受试者相比，与初发和慢性HIV-1感染的发展相关的肺微生物组的变化，以及是否可以通过使用HAART控制HIV-1病毒复制来缓解这些变化。第二个目标将评估有无PAH存在的慢性感染HIV-1受试者的肺微生物组的差异，以及HIV-1变异与可能影响病毒进化和微生物组的免疫反应之间的联系。在具体目标3中，将进行元基因组研究，以量化选定的感染HLV-1不同阶段的受试者的细菌谱系、基因和编码的功能特性。这些研究将促进我们对微生物群、先天免疫和获得性免疫改变与慢性肺部疾病发展之间的关系的理解。相关性(见说明)：识别HIV-1感染者和非感染者的肺微生物组将使我们能够了解在健康和疾病中人类肺中存在哪些微生物。这些知识将加强我们对这些微生物以及由此产生的适应性和先天免疫反应在HLV-1感染的非感染性肺部并发症发展中的作用的理解。了解健康人群和HIV-1感染者的肺部微生物群将有望有助于确定疾病进展的预测因素和治疗目标，以便转化为更好的预防和治疗策略。

DESCRIPTION (provided by applicant): The lung has been recognized as one of the main targets of infectious and non-infectious complications of human Immunodeficiency virus type 1 (HIV-1) infection. Despite the initiation of HAART, pulmonary complications of H1V-1/AIDS continue to be a major cause of morbidity and mortality in HIV-1-infected patients. Defects in innate and adaptive immune responses increase the risk for the development of pneumonias caused by both pathogenic and opportunistic microorganisms in HIV-1-infected individuals. Following pneumonia, these individuals experience a decrement In lung function, which is not observed in HIV-1-uninfected populations. It remains unknown whether the deterioration of lung function or the development of chronic lung disease in the setting of HIV-1 infection is related to immunodeficiency, alteration in the lung microbiome and the subsequent development of chronic lung inflammation. Through our funded "Longitudinal Studies of HIV-Associated Lung Infections and Complications" program, we initiated a systematic analysis of nef sequences evolution in the lung and periphery using high-throughput sequencing platforms. These studies revealed interesting patterns of HlV-1 nef variants that are associated with HIV-1-related pulmonary arterial hypertension, a non-infectious complication of chronic HIV-1. With the advent of more highly advanced high-throughput sequencing technology, we can generate data sets of sufficient quality and depth that will allow us to make inferences as to how changes in disease stage influence the lung microbiota and affect the development and progression of HIV-1-related acute and chronic lung complications. Utilizing the tremendous expertise in the fields of HIV-1 pathogenesis, lung immunology, computational biology and bioinformatics present at the University of Colorado, we hypothesize that the immunodeficiency associated with l-ilV-1 infection leads to a broadening of the lung microbiome and that the inflammatory response to increased microbiota and HIV-1 variants will result in non- infectious chronic lung complications such as pulmonary arterial hypertension (PAH). In specific aim 1, we will determine the alterations in the lung microbiome associated with the development of both primary and chronic HIV-1 infection as compared to seronegative healthy control subjects and whether these alterations can be mitigated by controlling HIV-1 viral replication with HAART. The second aim will evaluate differences in the lung microbiome between chronically infected HIV-1 subjects with and without the presence of PAH and the association between HIV-1 variants and immunological responses that may affect virus evolution and the microbiome. In specific aim 3, metagenomic studies will be performed to quantify the bacterial lineages, genes, and encoded functional properties identified in the lung of selected subjects with varying stages of HlV-1 infection. These studies will advance our understanding ofthe relationship between alterations in the microbiome, innate and adaptive immunity, and the development of chronic lung disease. RELEVANCE (See instructions): Identification of the lung microbiome in HIV-1-infected and -uninfected individuals will enable us to learn which microbes are present in the human lung in health and disease. This knowledge will enhance our understanding of the role of these microbes and the resultant adaptive and innate immune responses in the development of noninfectious lung complications of HlV-1 infection. Understanding the lung microbiome in health and in subjects infected with HIV-1 will hopefully lead to the identification of predictors of disease progression and therapeutic targets for translation into better preventive and treatment strategies.