Genomic Analysis of Immunity and Lung Inflammation in HIV Infection

HIV 感染中免疫和肺部炎症的基因组分析

• 批准号: 8904713
• 负责人: KENNETH S KNOX
• 金额: $ 63.4万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8904713
• 关键词: Address; Aging; Alveolar Macrophages; Anti-Retroviral Agents; Antigens; Area; Automobile Driving; Back; Bioinformatics; Blood; Blood specimen; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Characteristics; Chest; Chronic; Chronic Obstructive Airway Disease; Clinical; Cross-Sectional Studies; Cytomegalovirus; DNA; Data; Data Analyses; Development; Evaluation; Failure; Follow-Up Studies; General Population; Genomics; Goals; HIV; Health; Highly Active Antiretroviral Therapy; Immune; Immunity; Immunologic Deficiency Syndromes; Immunologics; Inflammation; Inflammatory; Investigation; Irrigation; Lead; Liquid substance; Longterm Follow-up; Lung; Lung Inflammation; Lung diseases; Lymphocyte; Lymphocyte Function; Macrophage Activation; Measures; Mediating; Molecular; Patients; Phenotype; Physicians; Plant Roots; Population; Pulmonary Hypertension; Pulmonary function tests; Qualifying; Questionnaires; Recording of previous events; Recruitment Activity; Risk; Sampling; Scientist; T cell response; T-Lymphocyte; Therapy Evaluation; Time; Viral; Viral Load result; Viral Proteins; Virus; Virus Diseases; Visit; Work; X-Ray Computed Tomography; chemokine; cohort; cytokine; data management; experience; follow-up; immunosenescence; improved; longitudinal analysis; macrophage; microbiome; nano-string; peripheral blood; premature; reconstitution; respiratory; response; restoration; senescence; transcriptome sequencing; viral DNA; viral RNA; virome

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.

描述（由申请人提供）：肺部室HIV感染的特征是慢性炎症和严重的免疫危险。尽管在高度活性抗逆转录病毒疗法（HAART）上可以改善，但这些患者仍然容易受到肺部疾病的影响， 特别是那些由慢性炎症介导的。此外，由于一种称为免疫衰老的现象或加速衰老而导致的淋巴细胞功能不佳，因此免疫重构经常以功能不佳的特征。免疫衰老通常是由慢性抗原刺激引起的，通常是病毒。在这方面，我们已经表明，HAART患者的肺部可以持续存在。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，我们假设整个HIV或HIV蛋白的持续性抗原刺激会导致免疫感染的肺表型和慢性肺部炎症，从而导致与HIV感染相关的晚期并发症。为了解决这一假设，我们将利用两个自2000年以来招募的艾滋病毒感染受试者的纵向纵向群体来检查对HAART的炎症和免疫学反应。我们将招募这些受试者进行长期随访，以评估基线，早期的HAART发现或晚期HAART发现预测长期HIV HIV肺并发症的发展。为了实现我们的目标，我们提出了以下特定目的：（1）评估使用呼吸问卷，肺功能测试，胸部CT成像和支气管腔液的治疗治疗三年或更长时间的HIV感染受试者。 （2）通过测量支气管肺泡灌洗液和血液中的细胞细胞HIV和细胞HIV RNA和HIV DNA，评估长期HAART患者的肺和外周血HIV病毒载量和病毒蛋白。 （3）在长期HAART后使用纳米肌的转录组分析肺和血液标本的转录组分析后，在基因组水平上评估HIV感染受试者的肺部炎症。 （4）通过测量细胞激活者，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HAART受试者的免疫和炎症潜力。鉴于我们研究了感染HIV的受试者的悠久历史，我们拥有大量的基线HIV人群，其基线临床和免疫学特征明确，这为我们提供了一个独特的机会，可以查看纵向长期随访。由于慢性炎症可能是长期HIV感染中大多数肺并发症的根源 工作可能对这些患者的管理具有广泛的影响。