HIV/TB Interaction in the Lung

HIV/结核病在肺部的相互作用

• 批准号: 7104244
• 负责人: Michael D. Weiden
• 金额: $ 46.88万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7104244
• 关键词: CD40 molecule; Mycobacterium tuberculosis; alveolar macrophages; antisense nucleic acid; bronchoscopy; cell adhesion molecules; cell cell interaction; clinical research; elastases; gene induction /repression; genetically modified animals; human immunodeficiency virus 1; human subject; laboratory mouse; lung; lung lavage; macrophage; microorganism interaction; mixed tissue /cell culture; neutrophil; nucleic acid repetitive sequence; oligonucleotides; septicemia; transcription factor; transfection /expression vector; tuberculosis; virus replication

DESCRIPTION (provided by applicant): HIV/TB interaction in the lung has focused on regulation of HIV-1 replication in alveolar macrophages (AM), the major source of viral replication in tuberculosis (TB). Work performed in this laboratory has demonstrated: 1) Production of inhibitory C/EBPbeta is an interferon (IFN) effect. It is also induced by other innate immune mediators such as SP-a. Once expressed, inhibitory C/EBPbeta suppresses HIV-1 replication and most proinflammatory cytokine promoters in resting AM. 2) As monocytes differentiate to macrophages, they gain the ability to produce a dominant negative C/EBPbeta transcription factor. 3) During TB, contact between lymphocytes and AM drives high-level HIV-1 replication in AM. Both lymphocyte/AM contact and cytokines are required for maximal LTR activation. Lymphocyte/AM contact down-regulates the dominant negative C/EBPbeta, de-repressing the HIV-1 LTR; while cytokines activate NF-kappaB, stimulating the HIV-1 LTR. 4) In mice, CD40 expression is required for de-repression during sepsis. Preliminary data now demonstrate that PU.1 and CREM are expressed in resting AM but not during TB. Both PU.1 and CREM are transcriptional repressors in other systems. In addition, a subset of AIDS patients with TB demonstrates neutrophil (PMN) predominant inflammation. PMN stimulate HIV-1 replication and mutation in vivo and in vitro. Full induction of HIV-1 replication and LTR function requires PMN contact and soluble factors. Like lymphocytes, PMN express CD40L and CD28. Unlike lymphocytes, PMN express LFA- 1, which binds macrophage ICAM-1, and PMN-derived peroxide is a soluble factor that activates NF-kappaB. PMN contact down-regulates inhibitory C/EBPbeta, CREM and PU. 1 in AM. TB patients have elevated levels of soluble ICAM-1, which recruits CD40L to PMN lipid rafts. Antibodies to CD40L, CD28 and CD11a inhibit the activity of PMN lipid rafts. PMN lipid rafts and cross-linking antibodies to CD40, B7 and ICAM-1 aggregate macrophage CD40, B7 and ICAM-1 and abolish inhibitory C/EBPbeta expression. These data led to the hypothesis that inhibitory C/EBPbeta is one of multiple repressors inhibiting HIV LTR activity in resting AM. Further, PMN are a cellular component of the innate immune response that can de-repress the LTR by cellular contact and activate the LTR by soluble factors. This two-step process contributes to high-level HIV-1 replication in AM during opportunistic infection. This proposal will investigate the role of PU. 1 and CREM as inhibitors of HIV-1 replication in AM and the role of PMN in enhancing HIV-1 replication in the lung.

描述（由申请方提供）：肺中的HIV/TB相互作用集中于肺泡巨噬细胞（AM）中HIV-1复制的调节，AM是结核病（TB）中病毒复制的主要来源。本实验室的工作证明：1）抑制性C/EBP β的产生是干扰素（IFN）的作用。它也由其他先天免疫介质如SP-a诱导。一旦表达，抑制性C/EBP β抑制HIV-1复制和大多数促炎细胞因子在静息AM中的启动子。2)随着单核细胞分化为巨噬细胞，它们获得产生显性负性C/EBP β转录因子的能力。3)在TB期间，淋巴细胞和AM之间的接触驱动AM中的高水平HIV-1复制。淋巴细胞/AM接触和细胞因子都是最大LTR激活所必需的。淋巴细胞/AM接触下调显性阴性C/EBP β，解除HIV-1 LTR的抑制;而细胞因子激活NF-κ B，刺激HIV-1 LTR。4)在小鼠中，CD 40表达是脓毒症期间去抑制所必需的。目前的初步数据表明，PU.1和CREM在静息AM中表达，但在TB期间不表达。PU.1和CREM都是其他系统中的转录抑制因子。此外，一个子集的艾滋病患者结核病表现出中性粒细胞（PMN）为主的炎症。PMN在体内和体外刺激HIV-1复制和突变。HIV-1复制和LTR功能的完全诱导需要PMN接触和可溶性因子。与淋巴细胞一样，PMN表达CD 40 L和CD 28。与淋巴细胞不同，PMN表达LFA- 1，其结合巨噬细胞ICAM-1，并且PMN衍生的过氧化物是激活NF-κ B的可溶性因子。PMN接触下调抑制性C/EBP β、CREM和PU。1在上午TB患者具有升高的可溶性ICAM-1水平，其将CD 40 L募集到PMN脂筏。抗CD 40 L、CD 28和CD 11 a抗体可抑制PMN脂筏的活性。PMN脂筏和CD 40、B7和ICAM-1的交联抗体聚集巨噬细胞CD 40、B7和ICAM-1，并消除抑制性C/EBP β表达。这些数据导致了这样的假设，即抑制性C/EBP β是在静息AM中抑制HIV LTR活性的多种阻遏物之一。此外，PMN是先天免疫应答的细胞组分，其可以通过细胞接触解除抑制LTR并通过可溶性因子激活LTR。这两个步骤的过程有助于高水平的HIV-1复制AM在机会性感染。本提案将研究PU的作用。1和CREM作为AM中HIV-1复制的抑制剂以及PMN在增强肺中HIV-1复制中的作用。