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，尽管对潜在的易感机制仍知之甚少。肺先天免疫宿主防御部分由效应细胞如肺泡巨噬细胞（AM）介导，所述效应细胞通过特异性表面受体如补体受体、清道夫受体、β-葡聚糖受体、Toll样和LPS受体（CD 14）和甘露糖受体识别病原体相关分子模式（PAMP）。本实验室先前的数据表明，HIV-1感染损害AM甘露糖受体介导的吞噬功能，这可能部分导致宿主对肺部机会性病原体如卡氏肺孢子虫、卡氏梭菌的易感性。neoformans和M.结核认识到NF-kB/I-kB信号通路在宿主细胞对感染性攻击的应答中的重要性，初步数据现在显示HIV引起甘露糖受体介导的NF-kB信号通路的特异性改变。本研究将从NF-kB/I-kB信号通路的角度进一步探讨HIV对AM天然免疫受体功能的影响。该建议的中心假设是，HIV改变AM先天受体介导的NF-κ B/I-κ B信号转导途径，这可能会损害对肺部病原体攻击的有效先天免疫应答，并导致宿主对机会性感染的易感性。利用来自健康个体的AM，这些研究将通过关注以下具体目标来阐明HIV介导的NF-κ B/I-KB信号失调的机制：具体目标#1：确定HIV-1对AM甘露糖受体介导的NF-κ B核转位的影响和特异性。具体目标#2：检查特定HIV-1基因产物对甘露糖受体介导的NF-κ B信号传导的作用（使用外源HIV-1蛋白和AAV载体递送env、达特、vpr、nef）。具体目标#3：通过检测上游信号分子蛋白激酶C、Rho GT3和PI-3激酶，确定HIV介导的甘露糖受体介导的NF-κ B信号失调水平。明确AM固有功能的特异性损伤将为开发新的增强局部免疫功能的药物提供合理的基础，从而降低AIDS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.