Tracheobronchial mucociliary dysfunction in HIV patients

项目概要： 细菌性肺炎仍然是HIV感染患者的一种重要合并症，尽管抗- 逆转录病毒疗法成功地恢复了CD 4细胞计数。艾滋病毒患者表现出微生物增加 下呼吸道和微生物植物群的定殖类似于在具有受损呼吸道的疾病中观察到的。 粘液纤毛清除（MCC），如囊性纤维化和COPD。艾滋病患者表现出鼻功能受损 粘膜纤毛清除率由于调节鼻MCC的生理机制与气管支气管MCC相似， MCC认为，HIV也可能抑制这一点。MCC装置的三个主要部件是， 粘液层、纤毛搏动和促进纤毛搏动的纤毛周围气道表面液体层。囊性 纤维化跨膜传导调节因子（CFTR）在纤毛周围气道的调节中起着关键作用 表面液体。我们的初步数据表明，HIV蛋白达特和gp 120可以抑制 MCC装置。HIV达特和香烟烟雾通过共同途径抑制CFTR的生物合成和功能 涉及TGF-β信号传导。此外，HIV达特和香烟烟雾协同作用，导致叠加抑制 CFTR功能。CFTR mRNA的抑制不是由于转录抑制，并强烈假定 miRNA介导的转录后基因沉默的作用。HIV gp 120与香烟烟雾抑制 基线纤毛搏动。这是很重要的，因为60%的艾滋病毒患者也吸烟。β-2-肾上腺素能 主要用作支气管扩张剂的受体激动剂可以恢复纤毛搏动和CFTR功能（如果CFTR 可以恢复可用性），从而恢复MCC。 基于这些观察，Aim 1将阐明miRNA介导的基因沉默在CFTR中的作用。 通过TGF-β抑制并鉴定参与的miRNAs。目标2将确认艾滋病毒患者表现出 CFTR生物合成减少，这可能是由于TGF-β1水平增加。我们还将确认艾滋病毒 患者表现出抑制睫状体搏动，这可以通过常规使用的β2-激动剂恢复。 作为支气管扩张剂用于哮喘和COPD等气道疾病。这些目标将共同审查 与HIV患者细菌性肺炎增加相关的基本分子机制， 测试治疗方法，以恢复这些患者的MCC装置的组件。该提案 目标将解决工作组确定的主要基础研究科学差距之一，即， “HIV、炎症、ART、合并感染和传统风险因素在HIV相关疾病进展中的相互作用， HLB疾病”，并确定治疗线索，以恢复MCC并降低发病率 HIV感染者的细菌性肺炎

PROJECT SUMMARY: Bacterial pneumonia continues to be an important comorbidity in HIV- infected patients even though anti- retrovial therapy has succeded in restoring CD4 cell counts. HIV patients demonstrate increased microbial colonization of the lower airways and the microbial flora is similar to that observed in diseases with impaired mucociliary clearance (MCC) like cystic fibrosis and COPD. HIV patients demonstrate impaired nasal mucociliary clearance. Since the physiological mechanisms regulating nasal MCC is similar to tracheobronchial MCC it is possible that HIV suppresses this as well. The three principal components of the MCC apparatus are, a mucus layer, ciliary beating and a periciliary airway surface liquid layer that facilitates ciliary beating. cystic fibrosis transmembrane conductance regulator (CFTR) plays a pivotal role in regulating the pericilary airway surface liquid. Our preliminary data show that HIV protiens Tat and gp120 can suppress components of the MCC apparatus. HIV Tat and cigarette smoke suppress CFTR biogenesis and function via a common pathway involving TGF-β signaling. Moreover, HIV Tat and cigarette smoke synergize to cause an additive suppression of CFTR function. Suppression of CFTR mRNA is not due to transcriptional suppression and strongly posits a role for miRNA mediated post-transcriptional gene silencing. HIV gp120 and cigarette smoke suppress baseline ciliary beating. This is significant since 60% of HIV patients also smoke tobacco. Beta-2-adrenergic receptor agonists primarily used as bronchodilators can restore ciliary beating and CFTR function (if CFTR availabiltiy can be restored) thereby restoring MCC. Based on these observations, Aim 1 will elucidate the role of miRNA mediated gene silencing in CFTR suppression by TGF-beta and identify the miRNAs involved. Aim 2 will confirm that HIV patients demonstrate decreased CFTR biogenesis and this is possibly due to increased TGF-β1 levels. We will also confirm that HIV patients demonstrate suppressed ciliary beating and this can be restored by β2-agonists that are routinely prescribed as bronchodilators in airway diseases like asthma and COPD. Together, these aims will examine basic molecular mechanisms relating to increased bacterial pneumonia in HIV patients while simultaneously testing therapeutic approaches to restore components of the MCC apparatus in these patients. The proposal aims will address one of the major basic research scientific gaps identified by the Working group namely, “Interplay of HIV, inflammation, ART, co-infections, and traditional risk factors in the progression of HIV-related HLB diseases”, for RFA-HL-14-029, and identify therapeutic leads to restore MCC and decrease the incidence of bacterial pneumonia in HIV patients.