NeuroAIDS Therapeutics-Targeting Immune Polarization of Macrophages in CNS

描述（由申请方提供）：中枢神经系统（CNS）的HIV感染是神经认知障碍治疗以及从CNS储库中根除HIV感染的重要挑战。中枢神经系统感染宿主的根除可能不仅对治疗认知功能障碍有益，而且对治疗HIV感染也有益。很明显，神经认知功能障碍是HIV感染者生存的负面预测因素，表明病毒持续存在和/或发病机制的共同机制促进免疫缺陷和神经认知功能障碍。在这两种疾病的交叉点是巨噬细胞，其中改变的免疫极化可以抑制抗病毒免疫反应，同时，作为CNS中病毒感染的储存库，以及炎症和神经元损伤的来源。 该提案是由坦普尔大学两个NIMH支持的神经艾滋病相关中心（P30）（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（宾夕法尼亚心理健康研究中心，德怀特埃文斯，医学博士，项目主任）。CHOP/UPENN和Temple调查人员之间的讨论，包括Jay Rappaport博士。（坦普尔大学），特雷西·费舍尔-史密斯，博士（坦普尔大学），和史蒂芬D。医学博士道格拉斯，与马克·G的进一步互动刘易斯博士，Bioqual，已经导致了跨学科和转化计划项目申请的概念，研究了根除CNS中HIV感染宿主的治疗方法。该申请是多个PI提交：Jay Rappaport，Ph.D.（相应的PI，天普大学）和Steven D.医学博士道格拉斯（儿童医院）。 该计划项目响应PAR-13 - 267（新型神经艾滋病治疗，临床前/临床综合计划（PO 1），题为"神经艾滋病治疗-靶向CNS中巨噬细胞的免疫极化"，汇集了三个项目和三个科学核心，分别设在三个机构。这些机构包括Temple University School of Medicine，Philadelphia，PA（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）、Bioqual Inc.、Rockville，MD（Core C）.在本项目中的每个项目中有许多重要的趋同概念，这些概念支持本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免疫功能障碍和CNS和外周中HIV感染的持续性。一个关键的概念是CNS和外周之间的相互作用在HIV感染导致CNS疾病的重要性。这些过程在很大程度上集中于髓系内的改变，包括外周单核细胞、组织巨噬细胞和小胶质细胞。为了根除艾滋病毒感染的水库，我们提出了三个途径，有助于骨髓谱系的免疫极化的干预。这三种方法靶向以下途径：1）ATP水解，其中终产物腺苷是免疫抑制性的（项目1，Jay Rappaport，Ph.D.，项目负责人，坦普尔大学），2）cFMS信号传导，其中该受体的M-CSF和IL-34配体可能有助于异常的单核细胞/巨噬细胞稳态、免疫极化和受感染储库的存活，（项目2，Tracy Fischer-Smith，Ph.D.，项目负责人，坦普尔大学）和3）神经激肽-1受体信号传导，其中配体物质P似乎促进病毒感染、免疫极化、存活和单核细胞/巨噬细胞的CNS侵袭以及CNS炎性和持久性储库的建立（项目3，Steven D.医学博士道格拉斯，项目负责人，费城儿童医院/宾夕法尼亚大学）。在这个高度整合的项目中提出的研究中，我们在体外、离体以及最终在SIV感染的恒河猴中单独、联合以及在cART治疗的背景下研究了针对这些途径中的每一种的治疗方法。这些项目的目标和目的由一个管理核心（核心A; Jay Rappaport博士）支持。和医学博士道格拉斯，核心共同领导人），免疫病理学核心（核心B; Tracy Fischer-Smith，Ph.D.，核心领导人，坦普尔大学），以及非人类灵长类动物的核心（核心C;马克G。刘易斯博士，Bioqual，Inc.）。 预计该总体计划目标的成功完成将为治疗HIV感染和根除HIV宿主（包括CNS）做出重要贡献。预计，在此取得的进展以及针对预防性和治疗性疫苗的进一步信息努力，其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.