Pathways of HIV neurodegeneration and dimethyl fumarate (DMF/MMF) neuroprotection

HIV 神经变性和富马酸二甲酯 (DMF/MMF) 神经保护的途径

基本信息

批准号：
8338805
负责人：
ANNA ALDOVINI
金额：
$ 72.47万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-26 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8338805
关键词：
Acanthophis antarcticus toxin Aa c Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apoptosis Brain CCL2 gene CD14 gene CD4 Positive T Lymphocytes CX3CL1 gene CXCL12 gene Cell Adhesion Molecules Cells Chemotaxis Chronic Clinical Trials Controlled Study Disease Disease Progression Drug Delivery Systems Drug usage Elements Endothelial Cells Europe Excitatory Neurotoxins FCGR3B gene Fumaderm Fumarates Future Gene Expression Gene Expression Profile Genes HIV HIV Envelope Protein gp120 HIV Infections HIV therapy Human Immune Immune response In Vitro Individual Inflammation Inflammation Mediators Inflammatory Response Investigation Lead Macaca mulatta Macrophage Activation Mediating Microglia Modeling Multiple Sclerosis NQO1 gene Nerve Degeneration Neurocognitive Neuroglia Neurons Neuropathogenesis Neuroprotective Agents Neurotoxins Pathway interactions Patients Peripheral Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Phase III Clinical Trials Pilot Projects Production Psoriasis Research Personnel Role SIV Signal Pathway Stromal Cell-Derived Factor 1 T-Lymphocyte Tissues Vertebral column Viral Load result Virus Virus Replication antiretroviral therapy disability gene induction immune activation in vivo macrophage migration monocyte neuroinflammation neuroprotection neurotoxicity novel response

项目摘要

DESCRIPTION (provided by applicant): HIV-associated neurocognitive disorders (HAND) remain prevalent despite the use of antiretroviral therapy (ART), and CNS inflammation & neurodegeneration associated with HIV replication in macrophages/microglia remain as neuropathological features. Persistent systemic inflammation & monocyte activation, CNS inflammation, macrophage activation, correlate with HAND in patients on ART. Thus, although ART is the backbone of HIV therapy, there is a critical need for adjunctive therapies to suppress persistent inflammation and virus replication, and to decrease the high burden of HAND- associated disability. Accordingly, drugs that suppress inflammation and HIV replication systemically and within the CNS are especially attractive as adjunctive neuroprotectants. We are proposing a dual-investigator MPI study (Kolson, Aldvoni) to investigate a novel drug, dimethyl fumarate, (DMF, Fumaderm(R)), now in a phase III clinical trial for multiple sclerosis) as a candidate neuroprotectant for HAND. Using our HIV neurotoxicity model we found that DMF and its primary in vivo metabolite, MMF, suppress a) HIV replication, b) associated inflammatory responses, and c) neurotoxin production in monocyte- derived macrophages (MDM). DMF/MMF also d) induces monocyte antioxidant responses and e) suppresses chemotaxis. In addition, using transcriptome analyses of HIV-infected T lymphocytes and MDM, we also demonstrated that HIV reprograms host gene expression in a cell-dependent manner to modulate pathways of virus spread, inflammatory mediators, and apoptosis, which can intersect pathways of HIV/MDM neurotoxin production & neurodegeneration. Because DMF is orally-deliverable, CNS- penetrating, and minimally toxic, we hypothesize that DMF can be an effective neuroprotectant in HAND and we further hypothesize that transcriptome analyses can identify host pathways modified by DMF/MMF that underlie its neuroprotection. We will: 1) Define mechanisms of DMF/MMF suppression of HIV replication and MDM neurotoxin production by HIV replication and Tat expression~ 2) Define DMF/MMF effects on suppression of monocyte & macrophage activation through anti-oxidant responses & other pathways~ 3) Determine mechanisms of DMF/MMF modulation of monocyte chemotaxis & transendothelial migration~ and 4) Determine the ability of DMF/MMF to suppress monocyte activation and induce antioxidant responses in SIV-infected rhesus macaques. This should provide a rationale for a future clinical trial in HIV patients.

描述（由申请人提供）：尽管使用抗逆转录病毒疗法（ART），HIV相关神经认知障碍（HAND）仍然普遍存在，并且与巨噬细胞/小胶质细胞中HIV复制相关的中枢神经系统炎症和神经变性仍然是神经病理学特征。持续的全身炎症和单核细胞活化、中枢神经系统炎症、巨噬细胞活化与接受 ART 的患者的 HAND 相关。因此，尽管 ART 是 HIV 治疗的支柱，但迫切需要辅助治疗来抑制持续性炎症和病毒复制，并减轻 HAND 相关残疾的沉重负担。因此，在中枢神经系统内全身抑制炎症和 HIV 复制的药物作为辅助神经保护剂特别有吸引力。我们正在提议开展一项双研究者 MPI 研究（Kolson、Aldvoni），以研究一种新药富马酸二甲酯（DMF、Fumaderm(R)），目前正处于针对多发性硬化症的 III 期临床试验中）作为 HAND 的候选神经保护剂。使用我们的 HIV 神经毒性模型，我们发现 DMF 及其主要体内代谢物 MMF 抑制 a) HIV 复制，b) 相关炎症反应，以及 c) 单核细胞衍生巨噬细胞 (MDM) 中神经毒素的产生。 DMF/MMF 还 d) 诱导单核细胞抗氧化反应，e) 抑制趋化性。此外，利用HIV感染的T淋巴细胞和MDM的转录组分析，我们还证明HIV以细胞依赖性方式重新编程宿主基因表达，以调节病毒传播、炎症介质和细胞凋亡的途径，这可以与HIV/ MDM 神经毒素的产生和神经变性。由于 DMF 可以口服、具有中枢神经系统穿透性且毒性极小，因此我们假设 DMF 可以成为 HAND 中的有效神经保护剂，并且我们进一步假设转录组分析可以识别 DMF/MMF 修饰的宿主通路，这些通路是其神经保护作用的基础。我们将： 1) 定义 DMF/MMF 抑制 HIV 复制和 HIV 复制和 Tat 表达产生 MDM 神经毒素的机制~ 2) 定义 DMF/MMF 通过抗氧化反应和其他途径抑制单核细胞和巨噬细胞活化的作用~ 3 ) 确定 DMF/MMF 对单核细胞趋化性和跨内皮迁移的调节机制 ~ 和 4) 确定 DMF/MMF 抑制单核细胞活化和诱导抗氧化反应的能力感染 SIV 的恒河猴。这应该为未来在艾滋病毒患者中进行的临床试验提供依据。