Interferon-a drives peripheral activation and brain injury in chronic HIV

干扰素-a 促进慢性 HIV 患者的外周激活和脑损伤

• 批准号: 8329279
• 负责人: Lynn PULLIAM
• 金额: $ 34.2万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-18 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8329279
• 关键词: Accounting; Adherence; Brain; Brain Injuries; CD14 gene; Cells; Chemotaxis; Chronic; Comorbidity; Data; Disease; Disease Progression; FCGR3B gene; Frequencies; Gene Expression Profile; HIV; HIV Infections; Human; Immune; Immune response; Impaired cognition; In Vitro; Individual; Inflammation; Inflammatory Response; Interferon Activation; Interferon-alpha; Interferons; Link; Lipopolysaccharides; Macaca; Minocycline; Modeling; N-acetylaspartate; Nervous System Trauma; Neuraxis; Neuronal Dysfunction; Neuropathogenesis; Peripheral; Phenotype; Population; Proteins; Quality of life; Regulation; Research; Risk; Role; SIV; Spleen; T-Lymphocyte; Viral Load result; antiretroviral therapy; chemokine; cytokine; immune activation; monocyte; nervous system disorder; research study; response; white matter

DESCRIPTION (provided by applicant): There is substantial evidence that immune activation is the determining factor for disease progression and co-morbidities in HIV infection. Peripheral immune activation, which is triggered by HIV, impacts the function of T cells and monocytes. HIV-induced monocyte proteins have been investigated as markers of an activated state that is tied to neuropathogenesis in the CNS. This is supported by SIV macaque models pointing to immune responses in the periphery being linked to CNS damage. In humans, an activated peripheral monocyte phenotype correlates with lower N-acetylaspartate (NAA), which is linked to neuronal dysfunction. However, there remains considerable debate whether LPS, type 1 interferon (IFN) or other factors are the causative agents. Our research shows that monocytes from HIV-infected subjects have a type 1 IFN gene expression profile. It is our overall hypothesis that in HIV disease type 1 IFN is responsible for chronic immune activation, which is associated with disease progression including cognitive impairment. We will: 1) investigate a number of variables that could produce the IFN-induced monocyte phenotype, 2) define a new IFN- induced monocyte phenotype, CD169, 3) determine the impact of immune activation on chemotaxis and cytokine elaboration and 4) determine if monocyte activation enhances LPS tolerance. Understanding the mechanism for continued activation in chronically HIV-infected individuals is crucial for mitigating CNS damage. PUBLIC HEALTH RELEVANCE: In spite of availability, adherence and effective antiretroviral therapy, there are still individuals who carry an HIV detectable viral load as well as those who are treated with no detectable viral load and have HIV-associated neurological disorders (HAND). We will show that continued peripheral activation by IFN-? is detrimental to HIV-infected individuals. We will investigate several mechanisms to suppress activation including compounds directed against peripheral markers of activation and inflammation.

描述（由申请人提供）：有大量证据表明，免疫激活是HIV感染中疾病进展和合并症的决定因素。由HIV触发的周围免疫激活会影响T细胞和单核细胞的功能。已经研究了HIV诱导的单核细胞蛋白作为激活状态的标志物，该标志与CNS中的神经发病相关。这是由SIV猕猴模型指出的，指出与CNS损伤相关的外围的免疫反应。在人类中，活化的周围单核细胞表型与较低的N-乙酰天冬氨酸（NAA）相关，与神经元功能障碍有关。但是，有LPS，1型干扰素（IFN）或其他因素是因果剂。我们的研究表明，来自HIV感染受试者的单核细胞具有1型IFN基因表达谱。我们的总体假设是，在HIV疾病中，IFN造成了慢性免疫激活，这与疾病进展有关，包括认知障碍。我们将：1）研究可能产生IFN诱导的单核细胞表型的许多变量，2）定义一种新的IFN诱导的单核细胞表型，CD169，3）确定免疫激活对趋化性和细胞因子的影响的影响以及4）确定单核细胞激活是否增强LPS耐受性。了解长期感染HIV的个体继续激活的机制对于减轻CNS损伤至关重要。 公共卫生相关性：尽管有可用性，依从性和有效的抗逆转录病毒疗法，但仍有一些人承担可检测的HIV病毒载量，以及那些没有可检测的病毒载荷并患有HIV相关神经系统疾病的人（手）。我们将证明IFN-持续的外围激活？对感染HIV的个体有害。我们将研究几种抑制激活的机制，包括针对激活和炎症的外围标记的化合物。