Lung Microbiome and Pulmonary Inflammation/Immunity in HIV Infection

描述（由申请人提供）：人类免疫缺陷病毒（HIV）感染的肺室特征为慢性炎症和严重的免疫紊乱。虽然一些炎性变化可能是由于HIV在肺中的慢性刺激，但这些变化与肺病毒载量之间的相关性很差。因此，其他因素可能驱动肺部的慢性炎症状态。考虑到这些患者已知的免疫缺陷，呼吸道定植新的或数量增加的感染性病原体的可能性很大，很容易导致慢性炎症。因此，我们假设HIV感染受试者的肺部炎症和免疫环境与宿主微生物组直接相关，而不是肺部HIV负荷，与未感染受试者相比，所观察到的免疫缺陷导致肺部微生物组更加多样化，并且高效抗逆转录病毒治疗（HAART）使肺部微生物组恢复正常。我们将利用现有的大量支气管肺泡灌洗样本，开始探索正常志愿者和HIV感染受试者的肺部微生物组，并将其与局部肺部炎症的测量结果相关联。这些队列包括患有COPD的HIV感染受试者和在开始抗逆转录病毒治疗前接受研究并纵向随访6-12个月的受试者。我们还将前瞻性地研究从口咽到肺泡的整个呼吸道的微生物组，以确定上呼吸道中的发现是否可以预测下呼吸道微生物组。为了实现我们的目标，我们提出以下具体目标。(1)比较HIV感染者和正常志愿者之间的呼吸道微生物组;（2）直接关联HIV感染者和正常志愿者中呼吸道微生物组与肺部炎症环境之间的关系;（3）确定高效抗逆转录病毒治疗是否改变肺部微生物组和局部炎症反应;（4）比较HIV感染者和正常志愿者从口咽部到肺泡的呼吸道微生物组。深入分析将从16 s和18 s rRNA测序开始，以描绘肺部微生物的全貌。将对前瞻性鉴定的物种进行详细的宏基因组鸟枪测序，以表征可能直接影响肺部免疫和炎症环境的重要基因库。这些研究将极大地增强我们对健康和疾病中肺部环境的理解，并导致潜在的定义肺部稳态的新模型。 相关性（参见说明）：在这个项目中，我们将检查存在于HIV感染者肺部的微生物植物群，以确定他们与非HIV感染者之间在所发现的微生物类型上是否存在差异。这些研究将增加我们对正常细菌如何在我们的肺部定植影响健康和疾病的肺部环境的理解。

DESCRIPTION (provided by applicant): The lung compartment in Human Immunodeficiency Virus (HIV) infection is characterized by chronic inflammation and severe immunologic derangements. While some of the inflammatory changes may be due to chronic stimulation by HIV in the lung, correlation between these changes and the lung viral load is poor. Thus other factors are likely driving the chronic inflammatory state in the lung. Given the known immunodeficiency in these patients, colonization of the respiratory tract with new or increased numbers of infectious pathogens is highly likely and easily could be contributing to chronic inflammation. Thus we hypothesize that the lung inflammatory and immunologic environment in HIV-infected subjects is directly related to the host microbiome rather than the pulmonary HIV burden, that the immunodeficiency seen leads to a more diverse pulmonary microbiome compared to uninfected subjects, and that highly active antiretroviral therapy (HAART) returns the pulmonary microbiome towards normal. We will make use of a large existing cohort of bronchoalvoelar lavage samples to begin exploring lung microbiomes in normal volunteers and HIV-infected subjects and correlate these with measures of local pulmonary inflammation. These cohorts include HIV-infected subjects with COPD and those studied prior to starting antiretroviral and followed longitudinally for 6-12 months. We will also prospectively study the microbiome along the entire respiratory tract from the oropharynx to the alveoli to determine if what is found in the upper tract can predict lower respiratory microbiomes. To accomplish our goals we propose the following Specific Aims. (1) To compare the respiratory microbiome between HIV-infected subjects and normal volunteers; (2) To directly correlate the relationship between the respiratory microbiome and the pulmonary inflammatory milieu in HIV-infected subjects and normal volunteers; (3) To determine if highly active antiretroviral therapy alters the pulmonary microbiome and local inflammatory response; and (4) To compare the respiratory microbiome in HIV-infected subjects and normal volunteers from the oropharynx to the alveoli. In depth analysis will start with 16s and 18s rRNA sequencing to paint a broad picture of the microorganisms present in the lung. Detailed metagenomic shotgun sequencing will be performed on prospectively identified species to characterize significant gene pools which may directly impact the pulmonary immunologic and inflammatory milieu These studies will greatly enhance our understanding of the lung environment in both health and disease and lead to potential new models defining pulmonary homeostasis. RELEVANCE (See instructions): In this project we will be examining the microbiological flora present in the lung of HIV-infected subjects to determine if there is a difference between them and non HIV-infected subject in the types of organisms found. These studies will add to our understanding of how normal bacteria colonizing our lungs influence the lung environment in health and disease.