Genomic Analysis of Immunity and Lung Inflammation in HIV Infection

描述(申请人提供)：肺间隔室艾滋病毒感染的特征是慢性炎症和严重的免疫紊乱。虽然高效抗逆转录病毒疗法(HAART)取得了改善，但这些患者仍然容易患肺部疾病， 尤其是那些由慢性炎症介导的。此外，免疫重建通常以淋巴细胞功能低下为特征，这是由于一种称为免疫衰老或加速衰老的现象。免疫衰老是由慢性抗原刺激引起的，通常是由病毒引起的。在这方面，我们已经证明艾滋病毒可以在接受HAART的患者的肺部持续存在。重要的是，免疫衰老与慢性炎症状态有关。因此，在这个项目中，我们假设HIV或HIV蛋白持续的抗原刺激会导致免疫衰弱的肺部表型和慢性肺部炎症，这是导致与HIV感染相关的晚期并发症的原因。为了解决这一假设，我们将利用自2000年以来招募的两个具有良好特征的HIV感染受试者的纵向队列来检查对HAART的炎症和免疫反应。我们将招募这些受试者进行长期随访，以评估基线、早期HAART发现或晚期HAART发现是否预测长期HIV肺部并发症的发展。为了实现我们的目标，我们提出了以下具体目标：(1)使用呼吸问卷、肺功能测试、胸部CT成像和支气管肺泡灌洗来评估接受治疗三年或更长时间的HIV感染者的肺部并发症。(2)通过检测HAART患者肺、外周血中无细胞HIV病毒载量和肺泡灌洗液及血液中的HIV RNA和HIV DNA，评价HAART患者肺和外周血中HIV病毒载量和病毒量。(3)通过肺和血液标本的纳米串序列转录组分析，从基因组水平评估长期HAART后HIV感染者的肺部炎症反应。(4)通过检测细胞活化标志物、T细胞表型、细胞因子和趋化因子释放以及抗原特异性T细胞反应来评估长期接受HAART的受试者的免疫和炎症潜能。鉴于我们研究艾滋病毒感染者的长期历史，我们有大量的基线艾滋病毒人群，具有明确的基线临床和免疫学特征，这为我们提供了一个独特的机会来观察长期的纵向随访。由于慢性炎症可能是长期感染艾滋病毒的大多数肺部并发症的根源，因此 这项工作可能会对这些患者的管理产生广泛的影响。

DESCRIPTION (provided by applicant): The lung compartment HIV infection is characterized by chronic inflammation and severe immunologic derangements. While improvement is seen on highly active antiretroviral therapy (HAART), these patients still are susceptible to lung disease, especially those mediated by chronic inflammation. Furthermore, immune reconstitution is frequently characterized by poorly functioning lymphocytes due to a phenomenon called immunosenescence, or accelerated aging. Immunosenescence is caused by chronic antigenic stimulation, usually by viruses. In this regard, we have shown that HIV can persist in the lung in patients on HAART. Importantly, immunosenescence is associated with a chronic inflammatory state. Thus in this project we hypothesize that persistent antigenic stimulation by whole HIV or HIV proteins leads to an immunosenescent lung phenotype and chronic lung inflammation which contribute to the late complications associated with HIV infection. To address this hypothesis we will make use of two well characterized longitudinal cohorts of HIV-infected subjects we have recruited since 2000 to examine inflammatory and immunologic responses to HAART. We will recruit these subjects back for a longterm follow up visit to assess whether baseline, early HAART findings, or late HAART findings predict the development of long term HIV pulmonary complications. To accomplish our goals we propose the following Specific Aims: (1) To assess HIV-infected subjects who have been on treatment for three years or longer for pulmonary complications using a respiratory questionnaire, pulmonary function testing, chest CT imaging, and bronchoalveolar lavage. (2) To assess the pulmonary and peripheral blood HIV viral load and virome in patients on longterm HAART by measuring acellular HIV and cellular HIV RNA and HIV DNA in bronchoalveolar lavage fluid and blood. (3) To assess lung inflammation in HIV-infected subjects at the genomic level after longterm HAART using nanostring sequencing transcriptome analysis of lung and blood specimens. (4) To assess immune and inflammatory potential in subjects on long-term HAART by measuring cellular activation makers, T cell phenotypes, cytokine and chemokine release, and antigen specific T cell responses. Given our long history of studying HIV-infected subjects we have a large baseline HIV population with well-defined baseline clinical and immunologic characteristics which provide us a unique opportunity to look at longitudinal long term follow-up. Since chronic inflammation is likely at the root of most pulmonary complications in long term HIV infection, this work could have broad reaching implications on the management of these patients.