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）：灵长类动病毒的最引人注目的特征之一，将其与逆转录病毒区分开来的是它们感染包括巨噬细胞和小胶质细胞在内的非分散细胞的能力。然而，对巨噬细胞储存库在灵长类动物（例如HIV-1）的复制和致病性中的作用知之甚少。尽管大多数注意力集中在巨噬细胞储存库在HIV-1介导的神经毒性中的作用，但实际机制强调了HIV-1诱导的神经毒性毒性。在上一个资金期间，我们获得了证据表明，HIV-1指挥官在巨噬细胞中的细胞因子，以完成其复制周期的某些方面。这样一来，HIV-1以一种可能对病毒在巨噬细胞内持续存在的能力以及感染巨噬细胞介导神经毒素的能力的能力的能力可能会产生重要的后果。这些发现可以总结如下：1。HIV-1辅助蛋白NEF通过促进病毒传播的巨噬细胞调节可溶性因子的产生。 NEF通过与CD40信号通路相交来做到这一点。 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包膜糖蛋白诱导感染巨噬细胞的促炎细胞因子产生，并在此过程中调节感染巨噬细胞的持久性。在下一个资金期间，我们将扩展这些发现。具体而言，我们建议：目标1：确定HIV-1 NEF和包膜蛋白调节巨噬细胞功能的病毒效应域。 AIM 2：确定NEF和包膜调节巨噬细胞功能的细胞决定因素。 AIM 3：定义HIV-1 NEF和包膜如何通过感染的巨噬细胞影响病毒持续性和神经毒素的产生。这些研究将提供对强调巨噬细胞中病毒持续性的分子机制的基本见解，并通过感染的巨噬细胞诱导神经毒性。