Longtitudinal Studies of HIV-Associated Bacterial Pneumonia

描述(由申请人提供)： 全球已有3780万人感染了HIV-1，美国有120万HIV-1携带者。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。南非拥有世界2%的人口，是世界上30%的艾滋病毒/艾滋病患者(530万)的家园。在大多数患者中，HAART将血浆病毒载量降低到检测范围以下，增加了CD4+计数，并减少了机会性感染的发生率。肺部感染性并发症仍被认识到：细菌性肺炎、结核病、巨细胞病毒和卡介苗肺炎。我们假设细菌性肺炎发生在HAART时代，尽管发病率较低，并将增强局部HIV-1的复制和突变。目的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、PFT，并前瞻性跟踪他们进行4次年度访问。目的2将研究36例HIV-1阳性细菌性肺炎患者和72例HIV-1阳性对照，对受累/未受累肺叶进行支气管肺泡灌洗(BAL)。HIV-1将在受累和未受累的肺叶和血浆中进行定量，预期PMN的炎症可能会推动巨噬细胞HIV-1转录增加HIV-1RNA病毒载量，巨噬细胞中的RT-PCR，以及受累肺叶中包膜V3环突变和耐药性突变的增加。我们将用流式细胞术对肺和血液中的细胞进行表面标记。目的3将使用体外实验和BAL细胞来评估巨噬细胞与PMN的相互作用，以确定可能导致突变的反应性氧化物种损伤的机制。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，以及细菌性肺炎在受累/非受累肺叶间隔中引起的变化。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 以及HAART能否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容易导致HAART失败，以及是否应该在HAART上启动CD4+患者的肺炎，因为局灶性肺部炎症增加了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。我们将血浆、血清、PBMC(RNA、DNA、蛋白质)、BAL、受累/未受累肺段的BAL和痰冷冻并储存在-70度，以供与其他NHLBI受赠者合作研究。

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.