ALVEOLAR MACROPHAGE HOST DEFENSES

肺部感染是导致发病率和死亡率的主要原因。 与感染人类免疫缺陷病毒-1(HIV-1)有关。基座 关于肺泡巨噬细胞(AM)在 肺宿主防御，以及HIV-1可以感染AM，潜在的 这一建议的论点是，继承和获得性宿主因素 主要影响AM与HIV-1相互作用的方式 肺功能障碍的直接和/或间接决定因素 与HIV-1感染相关的宿主防御。在这方面， 我们的目标是了解遗传和后天获得的宿主因素 修改HIV-1与人AM相互作用的生物学，以研究机制 通过HIV-1感染AM导致肺内T细胞耗尽，以及 为了研究艾滋病毒-L和AM的相互作用可能如何被 修改AM的细胞内和/或细胞外环境 利用最近的一项发现，趋化因子受体作为一种共同的 HIV-1的受体，以及有效修改基因的策略 利用复制缺陷的重组腺病毒构建人AM全套系统 (Ad)媒介，我们建议使用一组主要的HIV-1分离株来 表型和共受体的使用，以及正常人群的特征队列 供体作为AM的来源，以评估：(1)联合受体在 来自不同个体的不同表型的HIV-1分离株； (2)AM感染HIV-1与AM诱导细胞凋亡的关系 T细胞通过Fas配体-Fas途径；以及(3)对基因的调节 与共受体表达和HIV-L感染相关的AM谱系 这项建议代表了两个组织的独特合作， 技能：康奈尔大学医学院小组的专业知识 关于AM生物学和Ad载体介导的基因转移；专业知识 亚伦·戴蒙德艾滋病研究中心关于艾滋病毒-1生物学的研究；以及 我们两个小组联合使用相关的生物试剂和 研究人群。

Pulmonary infections are a major cause of the morbidity and mortality associated with infection by human immunodeficiency virus-1 (HIV-1). Based on the knowledge that alveolar macrophages (AM) play a central role in pulmonary host defenses, and that HIV-1 can infect AM, the underlying thesis of this proposal is that inherited and acquired host factors that influence the manner in which AM interact with HIV-1 are major determinants, directly and/or indirectly, of the dysfunction of pulmonary host defenses that is associated with HIV-1 infection. In this context, our goals are to understand the inherited and acquired host factors that modify the biology of HIV-1 interaction with human AM, to study mechanisms by which HIV-1 infection of AM lead to T-cell depletion in the lung, and to examine how the interaction of HIV-l and AM may be interrupted by modifying the intracellular and/or extracellular environment of the AM. Capitalizing on the recent discovery that chemokine receptors serve as co- receptors for HIV-1, and strategies to efficiently modify the genetic repertoire of human AM using replication deficient, recombinant adenovirus (Ad) vectors, we propose to use a panel of primary HIV-1 isolates for phenotype and co-receptor usage, and a characterized cohort of normal donors to serve as a source of AM, to evaluate: (1) co-receptor usage on AM from different individuals by HIV-1 isolates with different phenotypes; (2) the association of HIV-1 infection of AM with AM-induced apoptosis of T-cells via the fas ligand-fas pathway; and (3) modulation of the genetic repertoire of AM relevant to.co-receptor expression and HIV-l infection. This proposal represents a unique collaboration of two groups with diverse skills: the expertise of the Cornell University Medical College group regarding AM biology and Ad vector-mediated gene transfer; the expertise of the Aaron Diamond AIDS Research Center regarding HIV-1 biology; and the combined access of our two groups to the relevant biologic reagents and study populations.