NeuroAIDS Therapeutics-Targeting Immune Polarization of Macrophages in CNS

描述（由申请人提供）：中枢神经系统（CNS）的HIV感染对神经认知障碍的治疗以及从中枢神经系统库中根除HIV感染都是一个重要的挑战。根除中枢神经系统感染库可能是有益的，不仅对治疗认知功能障碍，而且对治疗艾滋病毒感染的整体。很明显，神经认知障碍是HIV感染患者生存的一个阴性预测因子，这表明病毒持续存在和/或发病机制促进免疫缺陷和神经认知障碍的共同机制。巨噬细胞处于这两种疾病的交叉点，在那里改变的免疫极化可以抑制抗病毒免疫反应，同时，在中枢神经系统中作为病毒感染的储存库，以及炎症和神经元损伤的来源。该提案是两个NIMH支持的神经艾滋病相关中心（P30s）在天普大学（综合神经艾滋病中心，Kamel Khalili博士，项目主任）和宾夕法尼亚大学/儿童医院（宾夕法尼亚精神健康研究中心，Dwight Evans医学博士，项目主任）共同作用的结果。CHOP/UPENN与包括Jay Rappaport博士（天普大学）、Tracy fisher - smith博士（天普大学）和Steven D. Douglas医学博士在内的天普大学研究人员进行了讨论，并与Bioqual的Mark G. Lewis博士进行了进一步的互动，形成了跨学科和转化项目应用的概念，研究了根除CNS中HIV感染库的治疗方法。该申请是由多个PI提交的：Jay Rappaport博士（天普大学相应PI）和Steven D. Douglas医学博士（PI-儿童医院）。该项目响应PAR-13-267（新型神经艾滋病治疗，综合临床前/临床计划（PO1）），题为“神经艾滋病治疗-靶向中枢神经系统巨噬细胞的免疫极化”，汇集了三个项目和三个科学核心，分别位于三个机构。这些机构包括坦普尔大学医学院，费城，（项目1，项目2，核心A和核心B），费城儿童医院（项目3和Co-PI核心A），马里兰州罗克维尔的Bioqual公司（核心C）。在这个项目中的每个项目中都有一些重要的融合概念，这些概念支持了这个项目中提出的总体假设，即单核细胞/巨噬细胞谱系的免疫极化改变促进了免疫功能障碍和艾滋病毒感染在中枢神经系统和外周的持续存在。一个关键的概念是中枢神经系统和外周细胞之间的相互作用在HIV感染导致中枢神经系统疾病中的重要性。这些过程在很大程度上集中在髓系的改变上，包括外周单核细胞、组织巨噬细胞和小胶质细胞。为了根除HIV感染的储存库，我们提出了三个途径的干预，有助于骨髓谱系的免疫极化。这三种方法针对以下途径：1) ATP水解，其最终产物腺苷具有免疫抑制作用（项目1，Jay Rappaport博士，天普大学项目负责人）；2)cFMS信号传导，该受体的M-CSF和IL-34配体可能导致单核/巨噬细胞异常稳态、免疫极化和感染宿主的存活（项目2，Tracy Fischer-Smith博士，天普大学项目负责人）；3)神经激肽-1受体信号传导；其中，P物质似乎可以促进病毒感染、免疫极化、存活和单核/巨噬细胞的中枢神经系统入侵，以及中枢神经系统炎症性和持久性储存库的建立（项目3，Steven D. Douglas，医学博士，项目负责人，费城儿童医院/UPENN）。在这个高度整合的项目中提出的研究中，我们研究了针对这些途径的治疗方法，在体外，离体，最后在SIV感染的恒河猴中，单独，联合，以及在cART治疗的背景下。这些项目的目标和目的由行政核心（核心A； Jay Rappaport博士和Douglas医学博士，核心共同领导），免疫病理学核心（核心B； Tracy fisher - smith博士，核心领导，天普大学）以及非人灵长类核心（核心C； Mark G. Lewis博士，Bioqual, Inc.）提供支持。预计成功完成这一总体方案的目标，将对治疗艾滋病毒感染和根除包括中枢神经系统在内的艾滋病毒库作出重要贡献。预计这方面的进展将进一步为预防和治疗性疫苗提供信息，在这些疫苗中，暴露后佐剂方法可用于重新激活否则被抑制的免疫反应。

DESCRIPTION (provided by applicant): HIV infection of the central nervous system (CNS) represents an important challenge for both the treatment of neurocognitive disorders as well as the eradication of HIV infection from CNS reservoirs. The eradication of CNS reservoirs of infection will likely be beneficial, not only for treating cognitive dysfunction, but also for treament of HIV infection overall. It is clear that neurocognitive impairment is a negative predictor of survival in HIV infection, suggesting common mechanisms of viral persistence and/or pathogenesis promote both immune deficiency and neurocognitive impairment. At the intersection of both these disorders is the macrophage, where altered immune polarization can suppress antiviral immune reactions and at the same time, serve as a reservoir for viral infection in the CNS, as well as a source of inflammation and neuronal injury. This proposal is a result of a joint interactions between two NIMH supported NeuroAIDS related Centers (P30s) at Temple University (Comprehensive NeuroAIDS Center, Kamel Khalili, Ph.D., Program Director) and UPenn/Children's Hospital (Penn Mental Health Research Center, Dwight Evans, M.D., Program Director). Discussions between CHOP/UPENN and Temple investigators including Jay Rappaport, Ph.D. (Temple University), Tracy Fischer-Smith, Ph.D. (Temple University), and Steven D. Douglas, M.D., with the further interactions with Mark G. Lewis, Ph.D., Bioqual, have led to the conception of an interdisciplinary and translational program project application, investigating therapeutic approaches to eradicating HIV infected reservoirs in the CNS. The application is a multiple PI submission: Jay Rappaport, Ph.D. (Corresponding PI, Temple University) and Steven D. Douglas, M.D. (PI-Children's Hospital). This program project in response to PAR-13-267 (Novel NeuroAIDS Therapeutics, Integrated Preclinical/Clinical Program (PO1), entitled "NeuroAIDS Therapeutics-Targeting Immune Polarization of Macrophages in CNS," brings together three projects and three scientific cores, housed at three institutions. These institutions include Temple University School of Medicine, Philadelphia, PA, (Project1, Project 2, Core A and Core B), Children's Hospital of Philadelphia (Project 3 and Co-PI Core A), Bioqual Inc., Rockville, MD (Core C). There are a number of important converging concepts in each of the Projects within this program, which support the overarching hypothesis put forth in this program, that altered immune polarization of the monocyte/macrophage lineage promotes immune dysfunction and the persistence of HIV infection in the CNS and the periphery. A critical concept is the importance of interaction between the CNS and the periphery in HIV infection leading to CNS disease. These processes are centered, to a large degree, on alterations within the myeloid lineage, including peripheral monocytes, tissue macrophages, and microglia. In order to eradicate reservoirs of HIV infection, we propose the intervention within three pathways that contribute to the immune polarization of the myeloid lineage. These three approaches target the following pathways: 1) ATP hydrolysis, where the end product, adenosine, is immune suppressive (Project 1, Jay Rappaport, Ph.D., Project Leader, Temple University), 2) cFMS signaling, where M-CSF and IL-34 ligands for this receptor may contribute to abnormal monocyte/macrophage homeostasis, immune polarization, and survival of infected reservoirs, (Project 2, Tracy Fischer-Smith, Ph.D., Project Leader, Temple University) and 3) neurokinin-1 receptor signaling, where the ligand substance P appears to promote virus infection, immune polarization, survival, and CNS invasion of monocytes/macrophages and the establishment of CNS inflammatory and persistent reservoirs (Project 3, Steven D. Douglas, M.D., Project Leader, Children's Hospital of Philadelphia/UPENN). In the studies proposed in this highly integrated program project, we investigate therapeutic approaches targeting each of these pathways in studies, in vitro, ex vivo, and finally in SIV infected rhesus macaques, alone, in combination, and in the context of cART therapy. The goals and objectives of these projects are supported by an Administrative Core (Core A; Jay Rappaport, Ph.D. and Douglas, M.D., Core Co-Leaders), an Immunopathology Core (Core B; Tracy Fischer-Smith, Ph.D., Core Leader, Temple University), as well as a Non Human Primate Core (Core C; Mark G. Lewis, Ph.D., Bioqual, Inc.). It is anticipated that successful completion of the objectives of this overll program, will make important contributions toward the treatment of HIV infection and eradication of HIV reservoirs, including the CNS. It is anticipated that advances made here with further inform efforts aimed at preventive and therapeutic vaccines, where post-exposure adjuvant approaches could be employed to reactivate otherwise suppressed immune reactions.