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

描述（由申请人提供）：本提案的最终目标是确定HIV-1 （HIV）在中枢神经系统中持续存在的位点，评估这些位点的HIV特征和动态，并测试一种新的临床前方法来根除这些位点。原理：HIV感染和持续的主要靶细胞是t细胞和巨噬细胞。通过cART疗法，血液中感染HIV的t细胞数量已经下降到几乎无法检测到的水平；然而，在病毒抑制的个体中，持续的基于组织的HIV感染位点和这种感染的演变尚未得到很好的定义。停用cART会导致HIV病毒血症的复发，其病毒株在罕见的血液t细胞库中没有定义，这表明存在一种迄今尚未定义的基于组织的HIV库。HIV感染的巨噬细胞是HIV相关性痴呆（HAD）患者的主要病毒组织库，在HAD患者的大脑中发现了高水平的独特的脑特异性HIV形式。在cart介导的外周血可检测到的HIV脑疾病的完全调节的患者中发生了显著变化，与HIV感染相关的较轻的认知功能障碍综合征现在已被定义为HIV相关神经认知障碍（HAND）。艾滋病毒在HAND中可能发挥的作用尚未确定。随着动脉粥样硬化作为hiv感染患者的重要合并症的出现，血管性痴呆的变异可能变得越来越频繁，这暗示了一种潜在的新型hiv相关中枢神经系统发病机制。该计划的目标是确定在有充分记录的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的位点和亚种。考虑到在巨噬细胞中可能会发现一个重要的HIV储存库，一种抑制巨噬细胞感染并调节单核细胞分化以阻止正在进行的向病变组织迁移的新疗法将在各种体外系统中进行测试，包括功能性脑细胞培养。特异性目的1：鉴定和表征HIV-1在病毒抑制队列尸检组织中中枢神经系统和其他储存库中持续存在的系统细胞和遗传基础。特异性目标2：评估巨噬细胞定位的HIV-1库病毒变体在人巨噬细胞和脑神经元/星形胶质细胞培养中的生长和功能影响，并测试PA300的功能影响，PA300是一种新的HIV感染抑制剂和巨噬细胞分化调节剂。提出的研究将允许对接受cART治疗的患者的HIV库进行明确的描述，并为解决该库中巨噬细胞特异性成分的新型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.