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

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触发的外周免疫激活影响T细胞和单核细胞的功能。hiv诱导的单核细胞蛋白已被研究作为与中枢神经系统神经发病机制相关的激活状态的标记物。SIV猕猴模型支持这一观点，表明外周免疫反应与中枢神经系统损伤有关。在人类中，激活的外周单核细胞表型与较低的n -乙酰天冬氨酸（NAA）相关，这与神经元功能障碍有关。然而，脂多糖、1型干扰素（IFN）或其他因素是否为致病因子仍存在相当大的争议。我们的研究表明，来自hiv感染者的单核细胞具有1型IFN基因表达谱。我们的总体假设是，在HIV疾病1型中，IFN负责慢性免疫激活，这与包括认知障碍在内的疾病进展有关。我们将：1)研究一些可能产生IFN诱导的单核细胞表型的变量，2)定义一个新的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细化的影响，4)确定单核细胞激活是否增强LPS耐受性。了解慢性hiv感染者持续激活的机制对于减轻中枢神经系统损伤至关重要。

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.