HIV/TB Interaction in the Lung

描述（由申请人提供）：HIV/TB在肺部的相互作用主要集中在肺泡巨噬细胞（AM）中HIV-1复制的调节，AM是结核病（TB）病毒复制的主要来源。本实验室的工作已经证明：1)抑制C/ ebp β的产生是一种干扰素（IFN）效应。它也可由其他先天免疫介质如SP-a诱导。一旦表达，抑制性C/EBPbeta在静息AM中抑制HIV-1复制和大多数促炎细胞因子启动子。2)当单核细胞分化为巨噬细胞时，它们获得了产生显性负C/EBPbeta转录因子的能力。3)在结核病期间，淋巴细胞与AM之间的接触驱动AM中HIV-1的高水平复制。最大LTR激活需要淋巴细胞/AM接触和细胞因子。淋巴细胞/AM接触下调显性阴性C/EBPbeta，抑制HIV-1 LTR；而细胞因子激活NF-kappaB，刺激HIV-1 LTR。4)在小鼠中，CD40的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，而在TB期间不表达。PU.1和CREM在其他系统中都是转录抑制因子。此外，一部分艾滋病合并结核病患者表现出中性粒细胞（PMN）为主的炎症。PMN在体内和体外刺激HIV-1复制和突变。充分诱导HIV-1复制和LTR功能需要PMN接触和可溶性因子。与淋巴细胞一样，PMN表达CD40L和CD28。与淋巴细胞不同，PMN表达与巨噬细胞ICAM-1结合的LFA- 1， 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C/EBPbeta、CREM和PU。上午1点。结核病患者可溶性ICAM-1水平升高，可将CD40L招募到PMN脂筏。CD40L、CD28和CD11a抗体抑制PMN脂筏的活性。PMN脂质筏和CD40、B7和ICAM-1交联抗体聚集巨噬细胞CD40、B7和ICAM-1，并消除抑制C/EBPbeta的表达。这些数据导致了一种假设，即抑制C/EBPbeta是静息AM中抑制HIV LTR活性的多种抑制因子之一。此外，PMN是先天免疫反应的一个细胞组成部分，可以通过细胞接触来抑制LTR，并通过可溶性因子激活LTR。这两步过程有助于AM在机会性感染期间的高水平HIV-1复制。本提案将探讨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HIV-1在肺中的复制中的作用。

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.