Molecular Features of and Approach to the HIV CNS Reservoir Post cART

cART 后 HIV 中枢神经系统储库的分子特征和方法

基本信息

批准号：
9105808
负责人：
MICHAEL Shannon MCGRATH
金额：
$ 37.14万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-04 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9105808
关键词：
AIDS Dementia Complex ATP binding cassette transporter 1 Address Anti-Retroviral Agents Astrocytes Atherosclerosis Autopsy Biological Assay Blood Blood Vessels Brain Brain Diseases Cell Culture Techniques Cells Cerebrospinal Fluid Cessation of life Characteristics Chronic Comorbidity Computer Analysis Consensus Sequence DNA Data Development Disease Documentation Drops Encephalopathies Environment Evaluation Evolution Freezing Functional disorder Genetic Genetic Recombination Goals Growth HIV HIV Envelope Protein gp120 HIV Infections HIV-1 HIV-associated neurocognitive disorder Health Hereditary Disease High Density Lipoproteins Human Impaired cognition In Vitro Incubated Individual Infection Inflammatory LDL Cholesterol Lipoproteins Life Macrophage Activation Mediating Metabolism Molecular Molecular Cloning Neurocognitive Neurons Pathogenesis Pathologic Pathology Report Patients Pattern Peripheral Pharmaceutical Preparations Play Population Production RNA RNA Splicing Recording of previous events Recurrence Regimen Regulation Resistance Role SIV Sampling Site Structure Syndrome System T-Lymphocyte Testing Tissues Tropism Tube Variant Vascular Dementia Vascular Diseases Viral Viral Load result Viral reservoir Viremia base brain abnormalities brain cell cohort cytokine drug resistant virus genetic signature genome sequencing in vivo inhibitor/antagonist killings laser capture microdissection macrophage migration molecular dynamics monocyte neuronal survival novel novel therapeutic intervention novel therapeutics peripheral blood pre-clinical programs response treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The ultimate goal of this proposal is to identify sites of HIV-1 (HIV) persistence in the CNS, evaluate the characteristics and dynamics of HIV in these sites and test a novel preclinical approach for eradicating these sites. Rationale: The major target cells for HIV infection and persistence are T-cells and macrophages. With cART therapy, the number of HIV infected T-cells in the blood has dropped to virtually undetectable levels; however, sites of persistent tissue-based HIV infection and the evolution of that infection in virally suppressed individuals have not been well defined. Discontinuation of cART leads to recurrence of HIV viremia with viral strains not represented by those defined in the rare blood T-cell reservoir, suggesting the existence of a heretofore undefined tissue-based HIV reservoir. HIV infected macrophages have been implicated as a major viral tissue based reservoir in patients with HIV associated dementia (HAD) and unique brain-specific forms of HIV have been found at high levels in HAD patient brains. In patients with cART-mediated complete regulation of peripheral blood detectable HIV brain disease has changed significantly and the milder cognitive dysfunction syndromes associated with HIV infection have now been defined as HIV-associated neurocognitive disorders (HAND). The role that HIV might play in HAND has not yet been determined. With the emergence of atherosclerosis as a significant comorbidity in HIV-infected patients, it appears that a variation of vascular dementia may be becoming more frequent, implicating a potentially new type of HIV-associated CNS pathogenesis. The goal of this program is to define the sites and subspecies of HIV present in CNS and peripheral tissues in patients with well documented histories of cART associated viral suppression. Given the likelihood that a significant reservoir of HIV will be found in macrophages, a novel therapeutic that inhibits infection of macrophages and regulates monocyte differentiation so as to block ongoing migration into diseased tissues will be tested in a variety of in-vitro systems including functional brain cell cultures. Specific AIM 1: To identify and characterize the systemic cellular and genetic basis for HIV-1 persistence in the CNS and other reservoirs in autopsy tissues from a virally suppressed cohort. Specific AIM 2: Evaluate macrophage-localized HIV-1 reservoir virus variants for growth and functional effects in human macrophage and brain neuron/astrocyte cultures, and test functional effects of PA300, a novel regulator of HIV infection inhibitor and macrophage differentiation in such assays. Studies proposed will allow a definitive description of the HIV reservoir in patients treated with cART and provide in vitro support for a novel therapeutic approach that addresses the macrophage specific component of this reservoir.

描述（由申请人提供）：该提案的最终目标是确定中枢神经系统中 HIV-1 (HIV) 持续存在的位点，评估这些位点中 HIV 的特征和动态，并测试一种根除这些位点的新型临床前方法。理由：HIV 感染和持续存在的主要靶细胞是 T 细胞和巨噬细胞。通过 cART 疗法，血液中感染 HIV 的 T 细胞数量已降至几乎无法检测到的水平；然而，持续性组织性艾滋病毒感染的部位以及病毒抑制个体中感染的演变尚未明确。停止 cART 会导致 HIV 病毒血症复发，其病毒株不是稀有血液 T 细胞储存库中定义的病毒株，这表明存在迄今为止未定义的基于组织的 HIV 储存库。 HIV 感染的巨噬细胞被认为是 HIV 相关痴呆 (HAD) 患者体内主要的病毒组织储存库，并且在 HAD 患者大脑中发现了高水平的独特的大脑特异性 HIV 形式。在cART介导的外周血完全调节的患者中，可检测到的HIV脑部疾病发生了显着变化，与HIV感染相关的轻度认知功能障碍综合征现已被定义为HIV相关神经认知障碍（HAND）。 HIV 在 HAND 中可能发挥的作用尚未确定。随着动脉粥样硬化成为 HIV 感染患者的一种重要合并症，血管性痴呆的变体似乎可能变得更加频繁，这暗示着一种潜在的新型 HIV 相关中枢神经系统发病机制。该计划的目标是确定具有 cART 相关病毒抑制史的患者中枢神经系统和外周组织中 HIV 的位点和亚种。鉴于巨噬细胞中可能存在大量 HIV 病毒，一种抑制巨噬细胞感染并调节单核细胞分化以阻止其持续迁移至患病组织的新疗法将在包括功能性大脑在内的各种体外系统中进行测试细胞培养物。具体目标 1：识别和表征 HIV-1 在中枢神经系统和来自病毒抑制队列的尸检组织中其他储存库中持续存在的系统细胞和遗传基础。具体目标 2：评估巨噬细胞定位的 HIV-1 储存病毒变异体对人巨噬细胞和脑神经元/星形胶质细胞培养物的生长和功能影响，并测试 PA300（一种 HIV 感染抑制剂和巨噬细胞分化的新型调节剂）的功能影响。拟议的研究将能够对接受 cART 治疗的患者的 HIV 储存库进行明确的描述，并为解决该储存库的巨噬细胞特异性成分的新型治疗方法提供体外支持。