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

描述（由申请方提供）：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为与CNS中神经发病机制相关的活化状态的标志物。这一点得到了SIV猕猴模型的支持，该模型指出外周的免疫应答与CNS损伤有关。在人类中，活化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，对于LPS、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，HIV感染者的单核细胞具有1型IFN基因表达谱。这是我们的总体假设，在HIV疾病1型IFN是负责慢性免疫激活，这是与疾病进展，包括认知障碍。我们将：1）研究可产生IFN诱导的单核细胞表型的许多变量，2）定义新的IFN诱导的单核细胞表型，CD 169，3）确定免疫活化对趋化性和细胞因子加工的影响，和4）确定单核细胞活化是否增强LPS耐受性。了解慢性HIV感染者持续激活的机制对于减轻CNS损伤至关重要。 公共卫生相关性：尽管抗逆转录病毒疗法的可获得性、坚持性和有效性，但仍有一些人携带可检测到的艾滋病毒载量，以及那些接受治疗但未检测到病毒载量并患有艾滋病毒相关神经系统疾病（HAND）的人。我们将表明，持续外周激活IFN-？对HIV感染者有害。我们将研究几种抑制活化的机制，包括针对活化和炎症的外周标记物的化合物。

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.