Alterations in Lung Microbiome in Acute and Chronic HIV infection

描述（由申请人提供）：肺已被认为是人类免疫缺陷病毒1型（HIV-1）感染的传染性和非传染性并发症的主要靶点之一。尽管开始了HAART治疗，但h1 -1/艾滋病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。先天和适应性免疫反应的缺陷增加了hiv -1感染者由致病性和机会性微生物引起的肺炎发展的风险。肺炎后，这些人的肺功能下降，这在hiv -1未感染人群中没有观察到。目前尚不清楚在HIV-1感染的情况下肺功能的恶化或慢性肺部疾病的发展是否与免疫缺陷、肺微生物组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，我们使用高通量测序平台启动了对肺部和周围nef序列进化的系统分析。这些研究揭示了与HIV-1相关的肺动脉高压（一种慢性HIV-1的非感染性并发症）相关的HIV-1 nef变异的有趣模式。随着更先进的高通量测序技术的出现，我们可以产生足够质量和深度的数据集，这将使我们能够推断疾病阶段的变化如何影响肺部微生物群，并影响hiv -1相关急性和慢性肺部并发症的发生和进展。利用科罗拉多大学在HIV-1发病机制、肺免疫学、计算生物学和生物信息学领域的大量专业知识，我们假设与l-ilV-1感染相关的免疫缺陷导致肺部微生物群的扩大，并且对微生物群和HIV-1变异增加的炎症反应将导致非感染性慢性肺部并发症，如肺动脉高压（PAH）。在特定目标1中，我们将确定与血清阴性的健康对照受试者相比，肺部微生物组中与原发性和慢性HIV-1感染发展相关的改变，以及是否可以通过HAART控制HIV-1病毒复制来减轻这些改变。第二个目的是评估慢性感染HIV-1患者肺部微生物组的差异，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关系。在特定的目标3中，将进行宏基因组研究，以量化在不同阶段的HlV-1感染的选定受试者的肺部鉴定的细菌谱系、基因和编码功能特性。这些研究将促进我们对微生物组改变、先天免疫和适应性免疫以及慢性肺部疾病发展之间关系的理解。相关性（见说明）：鉴定hiv -1感染和未感染个体的肺部微生物组将使我们能够了解健康和疾病的人体肺部中存在哪些微生物。这一知识将增强我们对这些微生物的作用的理解，以及由此产生的适应性和先天免疫反应在甲型肝炎病毒感染的非感染性肺部并发症的发展中。了解健康人群和HIV-1感染者的肺部微生物群，有望有助于确定疾病进展的预测因素和治疗靶点，从而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.