Longtitudinal Studies of HIV-Associated Bacterial Pneumonia

HIV 相关细菌性肺炎的纵向研究

基本信息

批准号：
8098933
负责人：
WILLIAM N ROM
金额：
$ 79.52万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-28 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8098933
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 Proliferation Cell Separation Cells Cessation of life Characteristics Chest Chronic Disease Clinical Cytomegalovirus DNA Detection Diagnosis Disease Drug resistance Drug usage 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 Lung Lung Inflammation Lymphatic Diseases Lymphocyte Mediating Medical Memory Meta-Analysis Morbidity - disease rate Mutation National Heart, Lung, and Blood Institute New York North America 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 RNA Regulatory T-Lymphocyte 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 interstitial macrophage men mortality peripheral blood prevent programs reconstitution research study resistance mutation respiratory response sex transcription factor transmission process

项目摘要

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 已感染全球 3780 万人，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%），发病率最高，为 32.7/10A5。南非人口仅占世界人口的 2%，但却拥有世界上 30% 的艾滋病毒/艾滋病感染者（530 万）。 HAART 可将大多数患者的血浆病毒载量降低至检测限以下，增加 CD4+ 计数，并降低机会性感染的发生率。肺部感染并发症仍然被认可：细菌性肺炎、肺结核、CMV 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，并每年对他们进行 4 次前瞻性随访。 AIM 2 将在每个地点对 36 名患有细菌性肺炎的 HIV-1+ 患者和 72 名 HIV-1+ 对照进行研究，并对受累/未受累肺叶进行支气管肺泡灌洗 (BAL)。将在受累和未受累的肺叶和血浆中对 HIV-1 进行定量，预计 PMN 炎症可能会驱动巨噬细胞 HIV-1 转录，增加 HIV-1 RNA 病毒载量、巨噬细胞中的 RT-PCR 以及增加包膜 V3 环突变和耐药突变在受累的肺叶中。我们将使用流式细胞术用表面标记来表征肺和血液中的细胞。 AIM 3 将使用体外实验和 BAL 细胞评估巨噬细胞-PMN 相互作用，以确定可能导致突变的活性氧化剂损伤的机制。我们将在开普敦评估 Treg 抑制功能，以确定 HAART 和 HIV-1 对 Treg 的影响，以及受累/未受累肺叶区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 CD4+ 水平低于正常水平时保留 >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会导致HAART失败，以及CD4+肺炎患者是否应该开始HAART，因为局灶性肺部炎症会增加HIV-1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 FACS 细胞分选来分离巨噬细胞、淋巴细胞和中性粒细胞以进行机制研究。我们将在 -70 度下冷冻并储存来自受累/未受累肺段的血浆、血清、PBMC（RNA、DNA、蛋白质）、BAL、以及痰液，以便与其他 NHLBI 受资助者进行合作研究。