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

描述(由申请人提供)：这项建议的最终目标是确定中枢神经系统中艾滋病毒-1(HIV)持续存在的地点，评估这些地点的艾滋病毒特征和动态，并测试一种新的临床前方法来根除这些地点。基本原理：HIV感染和持续感染的主要靶细胞是T细胞和巨噬细胞。通过CART疗法，血液中感染艾滋病毒的T细胞的数量已经下降到几乎无法检测到的水平；然而，基于组织的持续艾滋病毒感染的部位以及病毒抑制的个体中感染的演变还没有很好的定义。停用CART会导致HIV病毒血症的复发，病毒株不是稀有血液T细胞库中定义的病毒株，这表明到目前为止还没有确定的基于组织的HIV库的存在。HIV感染的巨噬细胞被认为是HIV相关性痴呆(HAD)患者的主要病毒组织储存库，在HAD患者的大脑中发现了高水平的独特的脑特定形式的HIV。在CART介导的外周血液完全调节的患者中，可检测到的HIV脑部疾病发生了显着变化，与HIV感染相关的较轻微的认知功能障碍综合征现在被定义为HIV相关神经认知障碍(HAND)。艾滋病毒在手中可能发挥的作用尚未确定。随着动脉粥样硬化在HIV感染患者中的出现，血管性痴呆的变异可能变得更加频繁，这可能意味着一种潜在的与HIV相关的新型中枢神经系统发病机制。该计划的目标是确定在有CART相关病毒抑制病史的患者的中枢神经系统和外周组织中存在的HIV部位和亚种。鉴于可能在巨噬细胞中发现大量的艾滋病毒储存库，一种新的治疗方法将在包括脑功能细胞培养在内的各种体外系统中进行测试，这种疗法可以抑制巨噬细胞的感染，并调节单核细胞分化，以阻止正在进行的向病变组织的迁移。特定目的1：从病毒抑制的队列中鉴定和描述HIV-1在中枢神经系统和其他尸检组织中持续存在的系统性细胞和遗传学基础。特异性目的2：评价巨噬细胞定位的HIV-1储存库病毒变异株对人巨噬细胞和脑神经元/星形胶质细胞培养的生长和功能的影响，并在此类实验中测试新的HIV感染抑制和巨噬细胞分化调节因子PA300的功能效应。建议的研究将允许明确描述接受CART治疗的患者中的艾滋病毒储存库，并为解决该储存库的巨噬细胞特异性成分的新的治疗方法提供体外支持。

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.