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，免疫激活是艾滋病毒感染中疾病进展和共病的决定因素。HIV引发的外周免疫激活会影响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为与中枢神经系统神经发病相关的激活状态的标志。这一点得到了SIV猕猴模型的支持，该模型指出外围的免疫反应与中枢神经系统的损伤有关。在人类中，激活的外周血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，关于内毒素、1型干扰素或其他因素是否是致病因素仍有相当大的争议。我们的研究表明，HIV感染者的单核细胞具有1型干扰素基因表达谱。我们的总体假设是，在艾滋病毒1型疾病中，干扰素负责慢性免疫激活，这与包括认知障碍在内的疾病进展有关。我们将：1)研究产生干扰素诱导的单核细胞表型的一些变量，2)定义一种新的干扰素诱导的单核细胞表型CD169，3)确定免疫激活对趋化和细胞因子分泌的影响，4)确定单核细胞激活是否增强了对内毒素的耐受。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.