Alveolar macrophage NF-kB signaling in HIV

描述(由申请人提供)：危及生命的机会性肺炎经常使HIV-1感染复杂化，尽管潜在的致病机制仍然知之甚少。肺泡巨噬细胞(AM)等效应细胞通过补体受体、清道夫受体、β-葡聚糖受体、Toll样和脂多糖受体(CD14)、甘露糖受体等表面受体识别病原体相关分子模式(PAMP)。本实验室以前的数据表明，HIV-1感染损害了AM甘露糖受体介导的吞噬功能，这可能在一定程度上导致宿主对卡氏肺假单胞菌、新生葡萄球菌和结核分枝杆菌等机会性肺部病原体的易感性。认识到核因子-kB/I-kB信号通路在宿主细胞对感染攻击的应答中的重要性，目前的研究表明，HIV可引起甘露糖受体介导的核因子-kB信号通路的特异性改变。在这项建议中，我们将进一步明确HIV对AM天然免疫受体功能的影响，重点是NF-kB/I-kB信号通路。这一建议的中心假设是HIV改变了AM固有受体介导的NF-kB/I-KB信号转导通路，这可能会损害对肺部病原体攻击的有效天然免疫反应，并有助于宿主对机会性感染的易感性。利用健康个体的AM，这些研究将通过以下特定目的来阐明HIV介导的NF-kB/I-KB信号失调的机制：特定目的1：明确HIV-1对AM甘露糖受体介导的NF-KB核转位的影响和特异性。具体目的#2：研究特定的HIV-1基因产物在甘露糖受体介导的NF-kB信号转导中的作用(使用外源HIV-1蛋白和AAV载体传递env、Tat、VPR、nef)。具体目的#3：通过检测上游信号分子蛋白激酶C、Rho GTP酶和PI-3激酶，确定HIV介导的甘露糖受体介导的NF-kB信号的失调程度。明确AM固有功能的特异性损害将为开发新的药物以增强局部免疫功能提供合理的基础，从而降低艾滋病患者肺部感染的发生率。

DESCRIPTION (provided by applicant): Life-threatening opportunistic pneumonia frequently complicates HIV-1 infection, although the underlying predisposing mechanisms remain poorly understood. Pulmonary innate immune host defense is mediated in part by effector cells such as alveolar macrophages (AM) which recognize pathogen-associated molecular patterns (PAMP) through specific surface receptors such as complement receptors, scavenger receptors, beta-glucan receptor, Toll-like and LPS receptor (CD 14), and mannose receptor. Previous data from this laboratory demonstrated that HIV-1 infection impairs AM mannose receptor-mediated phagocytic function which may in part contribute to host susceptibility to opportunistic pulmonary pathogens such as P. carinii, C. neoformans, and M. tuberculosis. Recognizing the importance of NF-kB/I-kB signaling pathway in host cell response to infectious challenge, preliminary data now show that HIV invokes a specific alteration in mannose receptor-mediated NF-KB signaling pathway. In this proposal, we will further define the influence of HIV on AM innate immune receptor function focusing on NF-kB/I-kB signal pathway. The central hypothesis for this proposal is that HIV alters AM innate receptor-mediated NF-kB/I-KB signal transduction pathways, which may impair an effective innate immune response to pulmonary pathogen challenge and contribute to host susceptibility to opportunistic infections. Employing AM from healthy individuals, these studies will elucidate the mechanism of HIV-mediated NF-kB/I-KB signal dysregulation by focusing on the following specific aims: Specific Aim #1: Define the influence and specificity of HIV-1 on AM mannose receptor-mediated NF-KB nuclear translocation. Specific Aim #2: Examine the role of specific HIV-1 gene products on mannose receptor-mediated NF-kB signaling (using exogenous HIV-1 proteins and AAV vector delivery of env, tat, vpr, nef). Specific Aim #3: Define the level of HIV-mediated dysregulation of mannose receptor-mediated NF-kB signaling by examining upstream signaling molecule Protein Kinase C, Rho GTPase and PI-3 kinase. Defining specific impairments in AM innate function will provide a rational basis for developing novel agents to augment local immune function, which could reduce the incidence of pulmonary infections in patients with AIDS.