Longtitudinal Studies of HIV-Associated Bacterial Pneumonia

HIV 相关细菌性肺炎的纵向研究

• 批准号: 7336698
• 负责人: WILLIAM N ROM
• 金额: $ 78.23万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7336698
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adherence; Affect; Africa South of the Sahara; Age-Years; Alveolar; Alveolitis; Anti-Retroviral Agents; Autopsy; Bacterial Pneumonia; Blood; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; CD4 Lymphocyte Count; CD8B1 gene; CXCL10 gene; California; Cell Separation; Cells; Cessation of life; Characteristics; Chest; Chronic Disease; Clinical; Cytomegalovirus; DNA; Daily; Detection; Diagnosis; Disease; Drug resistance; Drug usage; Enlargement of lymph nodes; Enrollment; Epidemic; Evolution; Failure; Feedback; Fever; Flow Cytometry; Freezing; Frequencies; Genetic Transcription; Granulomatous; HIV; HIV Infections; HIV-1; Heterosexuals; Highly Active Antiretroviral Therapy; Home environment; Homosexuals; Immune; Immunity; In Vitro; Incidence; Individual; Infection; Infiltration; Inflammation; Inflammatory; Injection of therapeutic agent; Intercellular adhesion molecule 1; Interleukin-15; Kaposi Sarcoma; Lead; Leukocyte Elastase; Leukocytes; Life; Lobe; Localized; Lung; Lung Inflammation; Lymphatic Diseases; Lymphocyte; Mediating; Medical; Memory; Meta-Analysis; Morbidity - disease rate; Mutation; New York; North America; Numbers; Opportunistic Infections; Oxidants; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Plasma; Pneumocystis carinii; Pneumonia; Population; Process; Production; Prophylactic treatment; Prospective Studies; Proteins; Pulmonary function tests; Questionnaires; Range; Rate; Reporting; Research; Research Personnel; Respiratory Tract Infections; Reverse Transcriptase Polymerase Chain Reaction; Risk; Sarcoidosis; Sentinel; Site; South Africa; Specimen; Speed; Sputum; Surface; Syndrome; T-Cell Activation; T-Cell Development; T-Lymphocyte; Tissues; Tuberculosis; V3 Loop; Variant; Viral; Viral Load result; Virus; Visit; Western Europe; cell motility; chemokine; cohort; cytokine; expectation; fluorouracil/melphalan/tamoxifen; interstitial; macrophage; men; mortality; peripheral blood; prevent; programs; reconstitution; research study; respiratory; response; sex; transcription factor; transmission process; viral RNA

DESCRIPTION (provided by applicant): HIV-1 has infected 37.8 million persons in the world and 1.2 million are living with HIV-1 in the U.S. New York has the most AIDS cases at 172,370 (18% of the U.S. total) and the highest case rate at 32.7/10A5. South Africa, which has <2% of the world's population, is home to 30% of all the people living with HIV/AIDS in the world (5.3 million). HAART reduces plasma viral load below the limits of detection in most patients, increases CD4+ counts, and reduces the incidence of opportunistic infections. Pulmonary infectious complications are still recognized: bacterial pneumonia, tuberculosis, CMV and PCP. We hypothesize that bacterial pneumonia occurs in the HAART era, albeit at a lower incidence, and will enhance local HIV-1 replication and mutation. AIM 1 will enroll 200 HIV-1+ patients each at New York and Cape Town, collect questionnaires, blood, sputum, PFT, and follow them prospectively for 4 annual visits. AIM 2 will study 36 HIV-1+ patients with bacterial pneumonia and 72 HIV-1 + controls at each site with bronchoalveolar lavage (BAL) of involved/uninvolved lobes. HIV-1 will be quantitated in involved and uninvolved lobes and plasma with the expectation that inflammation with PMNs may drive macrophage HIV-1 transcription increasing HIV- 1 RNA viral load, RT-PCR in macrophages and increased envelope V3 loop mutations and drug resistance mutations in involved lobes. We will characterize the cells in lung and blood with surface markers using flow cytometry. AIM 3 will evaluate macrophage-PMN interaction to determine the mechanisms of Reactive Oxidant Species damage that may cause mutations using in vitro experiments and BAL cells. We will evaluate Treg suppressive function in Cape Town to determine effects of HAART and HIV-1 on Tregs followed by changes caused by bacterial pneumonia in involved/uninvolved lobe compartments. This research will provide guidance on HAART therapy in HIV-1+ patients, particularly when the CD4+ level is preserved >250 cells/ml and whether HAART can prevent bacterial pneumonia, or alter its clinical features. We will also determine whether bacterial pneumonia predisposes to HAART failure, and if pneumonia in patients with CD4+ should be started on HAART because the focal lung inflammation increases HIV-1 replication and mutations. In this prospective study, we will also evaluate latent tuberculosis and other respiratory infections to determine their influence on the course of HIV-1 infection. We will use high-speed FACS cell sorting to separate macrophages, lymphocytes, and neitrophils for mechanistic studies. We will freeze and store at -70 degrees plasma, serum, PBMC (RNA, DNA, protein), BAL, from involved/uninvolved lung segments, and sputum for collaborative studies with other NHLBI grantees.

描述（由申请人提供）： HIV-1在世界上感染了3780万人，在美国有120万人感染HIV-1。纽约的艾滋病病例最多，为172,370例（占美国总数的18%），病例率最高，为32.7/10 A5。南非人口不到世界人口的2%，但却拥有世界上30%的艾滋病毒/艾滋病感染者（530万）。在大多数患者中，HAART将血浆病毒载量降低至检测限以下，增加CD 4+计数，并降低机会性感染的发生率。肺部感染并发症仍然是公认的：细菌性肺炎，结核病，巨细胞病毒和PCP。我们假设细菌性肺炎发生在HAART时代，尽管发病率较低，但会增强局部HIV-1复制和突变。AIM 1将在纽约和开普敦各招募200名HIV-1+患者，收集问卷、血液、痰液、PFT，并前瞻性随访4年。AIM 2将研究36例HIV-1+细菌性肺炎患者和72例HIV-1 +对照者，每个部位进行受累/未受累肺叶支气管肺泡灌洗（BAL）。将在受累和未受累叶和血浆中定量测定HIV-1，预期PMN炎症可能驱动巨噬细胞HIV-1转录，增加HIV- 1 RNA病毒载量，巨噬细胞中的RT-PCR和受累叶中包膜V3环突变和耐药性突变增加。我们将使用流式细胞术用表面标志物表征肺和血液中的细胞。目的3将评估巨噬细胞-中性粒细胞相互作用，以确定可能导致突变的反应性氧化物质损伤的机制，使用体外实验和BAL细胞。我们将在开普敦评价Treg抑制功能，以确定HAART和HIV-1对TCLB的影响，随后在受累/未受累肺叶室中由细菌性肺炎引起的变化。这项研究将为HIV-1+患者的HAART治疗提供指导，特别是当CD 4+水平低于 保存>250个细胞/ml以及HAART是否可以预防细菌性肺炎或改变其临床特征。我们还将确定细菌性肺炎是否易导致HAART失败，以及CD 4+患者的肺炎是否应该开始HAART治疗，因为局灶性肺部炎症会增加HIV-1的复制和突变。在这项前瞻性研究中，我们还将评估潜伏性结核病和其他呼吸道感染，以确定它们对HIV-1感染过程的影响。我们将使用高速流式细胞仪细胞分选分离巨噬细胞，淋巴细胞和嗜中性粒细胞的机制研究。我们将在-70 ℃下冷冻和储存血浆、血清、PBMC（RNA、DNA、蛋白质）、BAL、受累/未受累肺段和痰液，用于与其他NHLBI受资助者进行合作研究。