Activation of CD40 by HIV and Role in AIDS Dementia

HIV 激活 CD40 及其在艾滋病痴呆中的作用

• 批准号: 7474603
• 负责人: Mario Stevenson
• 金额: $ 33.73万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-29 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7474603
• 关键词: AIDS Dementia Complex; Appendix; Attention; Biology; Brain; CSF1 gene; Cell Communication; Cells; Cessation of life; Characteristics; Condition; Employee Strikes; Funding; Gene Silencing; Glycoproteins; HIV; HIV-1; Inflammatory; Interphase Cell; Lymphocyte; Mediating; Microglia; Molecular; Nature; Pathogenicity; Play; Primate Lentiviruses; Production; Protocols documentation; RNA Interference; Regulation; Research Personnel; Retroviridae; Role; Role playing therapy; Signal Pathway; Signal Transduction; Surface; T-Lymphocyte; TNF Receptor-Associated Factors; TNFRSF10A gene; TNFRSF10B gene; TNFRSF5 gene; TNFSF10 gene; Viral; Virus; Virus Diseases; cytokine; env Gene Products; insight; macrophage; monocyte; nef Protein; programs; receptor

DESCRIPTION (provided by applicant): One of the most striking characteristics of primate lentiviruses and one that distinguishes them from onco- retroviruses is their ability to infect non-dividing cells including macrophages and microglia. However, the role of the macrophage reservoir in the replication and pathogenicity of primate lentiviruses such as HIV-1 are poorly understood. While most of the attention has focused on the role of the macrophage reservoir in HIV-1-mediated neuronotoxicity, the actual mechanism underscoring HIV-1-induced neuronotoxicity is not well understood. In the previous funding period, we have obtained evidence that HIV-1 commandeers cellular factors in macrophages in order to complete certain aspects of its replication cycle. In doing so, HIV- 1 alters macrophage function in a way that may have important consequences for the ability of the virus to persist within macrophages and for the ability of infected macrophages to mediate neuronotoxicity. These findings can be summarized as follows: 1. The HIV-1 accessory protein, Nef regulates the production of soluble factors by macrophages that promote viral dissemination. Nef does so by intersecting the CD40 signaling pathway. 2. CD40 activation, or Nef expression in macrophages, induces the release of neuronotoxins. 3. The HIV-1 envelope glycoprotein induces pro-inflammatory cytokine production by infected macrophages and in doing so, regulates the persistence of the infected macrophage. In the next funding period, we will extend upon these findings. Specifically, we propose to: Aim 1: Identify the viral effector domains through which the HIV-1 Nef and envelope proteins regulate macrophage function. Aim 2: Identify the cellular determinants through which Nef and envelope regulate macrophage function. Aim 3: Define how HIV-1 Nef and envelope influence viral persistence and production of neuronotoxins by infected macrophages. These studies will provide fundamental insight into the molecular mechanisms underscoring viral persistence in macrophages and induction of neuronotoxicity by infected macrophages.

描述（由申请人提供）：灵长类慢病毒最显着的特征之一，也是它们与肿瘤逆转录病毒的区别之一，是它们感染非分裂细胞（包括巨噬细胞和小胶质细胞）的能力。然而，人们对巨噬细胞库在灵长类慢病毒（如 HIV-1）的复制和致病性中的作用知之甚少。虽然大多数注意力都集中在巨噬细胞库在 HIV-1 介导的神经毒性中的作用，但强调 HIV-1 诱导的神经毒性的实际机制尚不清楚。在之前的资助期间，我们获得了证据表明 HIV-1 征用巨噬细胞中的细胞因子以完成其复制周期的某些方面。在此过程中，HIV-1改变了巨噬细胞的功能，这种方式可能对病毒在巨噬细胞内持续存在的能力以及受感染的巨噬细胞介导神经毒性的能力产生重要影响。这些发现可概括如下： 1. HIV-1 辅助蛋白 Nef 调节巨噬细胞产生可溶性因子，从而促进病毒传播。 Nef 通过与 CD40 信号通路交叉来实现这一点。 2. CD40 激活，或巨噬细胞中的 Nef 表达，诱导神经毒素的释放。 3. HIV-1包膜糖蛋白诱导受感染巨噬细胞产生促炎细胞因子，并在此过程中调节受感染巨噬细胞的持续存在。在下一个资助期，我们将扩展这些发现。具体来说，我们建议： 目标 1：确定 HIV-1 Nef 和包膜蛋白通过其调节巨噬细胞功能的病毒效应域。目标 2：确定 Nef 和包膜调节巨噬细胞功能的细胞决定因素。目标 3：定义 HIV-1 Nef 和包膜如何影响病毒持久性和受感染巨噬细胞产生神经毒素。这些研究将为强调病毒在巨噬细胞中持续存在以及受感染的巨噬细胞诱导神经毒性的分子机制提供基础见解。