Antiretroviral-Induced Immune Recovery and the Central Nervous System

描述(申请人提供)：人类免疫缺陷病毒(HIV)感染全球4000多万人。有效的抗逆转录病毒疗法(ART)通过减少艾滋病毒复制和改善免疫功能，从根本上改变了艾滋病毒的病程。这降低了许多艾滋病毒相关并发症的发生率。尽管抗逆转录病毒治疗，但中枢神经系统(CNS)的并发症仍然存在，特别是艾滋病毒相关性神经认知障碍(HAND)。免疫恢复性疾病(IRD)可能是原因。当恢复的免疫系统对外来和自身抗原发生反应时，就会发生IRD，并可能导致实质性的组织损伤和死亡。在没有机会性病原体的情况下，IRD也可以对几个器官造成不太严重但临床上意义重大的损伤。该项目的主要目标将是比较ART诱导的脑脊液(CSF)和血液中的免疫恢复与神经心理(NP)表现的变化。我们建议通过研究40名艾滋病病毒感染者在开始新的抗逆转录病毒治疗方案前后来实现这一点。由于该项目将重点关注IRD的中枢神经系统并发症，一半的志愿者在治疗前会有手，另一半不会。研究访问将包括血液和脑脊液采样，标准化的神经医学和NP测试评估，以及有针对性的生物标记物小组。T细胞的表型、趋化因子受体的表达和对HIV多肽的功能反应将在血液和脑脊液来源的细胞中进行表征。总体假设是，免疫恢复对中枢神经系统的影响将在有手和没有手的艾滋病毒感染者之间有所不同。特别是，我们预计Hand将与激活的CD4+T细胞和CD8+效应记忆T细胞更多地归巢到中枢神经系统相关，在Hand组中，这些细胞的归巢将与NP表现的较少改善或恶化相关。该项目产生的数据将对HIV在大脑中的发病机制具有重要影响，并将支持该项目和未来项目的长期目标，以确定中枢神经系统IRD的预测因素和治疗方法。拟议的项目将与加州大学圣地亚哥分校(UCSD)现有的NIMH资助项目产生实质性的协同效应。公共卫生相关性：免疫介导的脑损伤具有重大的公共卫生相关性。了解轻度和中度IRD也将提高对HIV和其他神经炎性疾病神经系统并发症的发病机制的了解。这一知识可能会改善美国和资源更有限的地区(如撒哈拉以南非洲)的手部管理。这一知识将与艾滋病毒/艾滋病领域一个重要且仍有争议的问题直接相关，即开始治疗的最佳时间。

DESCRIPTION (provided by applicant): Human Immunodeficiency Viruses (HIV) infect more than 40 million people worldwide. Effective antiretroviral therapy (ART) has fundamentally altered the course of HIV disease by reducing HIV replication and improving immune function. This has led to reductions in the incidence of many HIV-associated complications. Complications of the central nervous system (CNS) have persisted despite ART, particularly HIV-associated Neurocognitive Disorder (HAND). Immune recovery disease (IRD) may be the reason. IRD occurs when the restored immune system reacts to foreign and self-antigens and can result in substantial tissue injury and death. IRD can also cause less severe - but clinically significant - injury of several organs in the absence of opportunistic pathogens. The primary objective of this project will be to compare ART-induced immune recovery in cerebral-spinal fluid (CSF) and blood to changes in neuropsychological (NP) performance. We propose to accomplish this by studying 40 HIV-infected individuals before and after initiation of new ART regimens. Because the project will focus on the CNS complications of IRD, half the volunteers will have HAND before treatment and half will not. Study visits will include sampling of blood and CSF, standardized neuromedical and NP testing assessments, and a targeted panel of biomarkers. T-cell surface phenotypes, chemokine receptor expression, and functional response to HIV peptides will be characterized in blood-derived and CSF-derived cells. The overall hypothesis is that the impact of immune recovery on the CNS will differ between HIV-infected individuals who have HAND and those who do not. In particular, we expect that HAND will be associated with greater homing of activated CD4+ T-cells and CD8+ effector memory T-cells into the CNS and that, within the HAND group, homing of these cells will be associated with less improvement or worsening of NP performance. The data generated by this project will have important implications for the pathogenesis of HIV in the brain and will support the longer term objective of this and future projects, to identify the predictors and treatment of IRD of the CNS. The proposed project will have substantial synergy with an existing NIMH-funded project at the University of California, San Diego (UCSD). PUBLIC HEALTH RELEVANCE: Immune-mediated brain injury has substantial public health relevance. Understanding mild and moderate IRD will also improve understanding of the pathogenesis of the neurological complications of HIV and other neuroinflammatory disorders. This knowledge may improve management of HAND in the U.S. and in more resource-limited settings, such as sub-Saharan Africa. This knowledge will have direct relevance for an important and still controversial question in the HIV/AIDS field, the optimal time to initiate therapy.