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: 8639210
• 负责人: KENNETH S KNOX
• 金额: $ 64.15万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8639210
• 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; Highly Active Antiretroviral Therapy; Image; 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; chemokine; cohort; cytokine; data management; experience; follow-up; immunosenescence; improved; longitudinal analysis; macrophage; microbiome; nano-string; peripheral blood; premature; public health relevance; 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）：肺室HIV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）有所改善，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疾病。此外，由于称为免疫衰老或加速衰老的现象，免疫重建的特点常常是淋巴细胞功能不良。免疫衰老是由慢性抗原刺激（通常是病毒）引起的。在这方面，我们已经证明，HIV 可以在接受 HAART 的患者肺部持续存在。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，我们假设整个 HIV 或 HIV 蛋白的持续抗原刺激会导致免疫衰老的肺部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，我们将利用自 2000 年以来招募的两个特征明确的 HIV 感染者纵向队列来检查对 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 结果或晚期 HAART 结果是否可以预测长期 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三年或更长时间肺部并发症治疗的 HIV 感染者。 (2)通过测量支气管肺泡灌洗液和血液中的非细胞HIV和细胞HIV RNA和HIV DNA来评估长期HAART患者的肺和外周血HIV病毒载量和病毒组。 (3) 使用肺和血液标本的纳米串测序转录组分析，在基因组水平上评估长期 HAART 后 HIV 感染者的肺部炎症。 (4) 通过测量细胞活化标志物、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，评估长期HAART受试者的免疫和炎症潜力。鉴于我们研究艾滋病毒感染者的悠久历史，我们拥有大量基线艾滋病毒人群，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进行纵向长期随访。由于慢性炎症可能是长期 HIV 感染中大多数肺部并发症的根源，因此 工作可能会对这些患者的管理产生广泛的影响。