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

• 批准号: 8669822
• 负责人: ANNA ALDOVINI
• 金额: $ 69.1万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/8669822
• 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 Targeting; 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

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），与HIV相关的神经认知障碍（手）仍然普遍存在，并且CNS炎症和神经变性与HIV复制相关的巨噬细胞/小胶质细胞中仍然是神经病理学特征。 持续的全身性炎症和单核细胞激活，中枢神经系统炎症，巨噬细胞激活，与手的手相关。 因此，尽管ART是艾滋病毒疗法的骨干，但辅助疗法迫切需要抑制持续的炎症和病毒复制，并减轻与手动相关的残疾负担的高负担。 因此，作为辅助性神经保护剂，系统地抑制炎症和HIV复制的药物特别有吸引力。 我们提出了一项双感染者MPI研究（Kolson，Aldvoni），以研究一种新型药物，即富马酸二甲基二甲基（DMF，Fumaderm（R）），该药物现在是在多发性硬化症的III期临床试验中，作为候选候选者。 使用我们的HIV神经毒性模型，我们发现DMF及其主要的体内代谢产物MMF，抑制A）HIV复制，B）相关的炎症反应以及C）单核细胞衍生的巨噬细胞（MDM）中的神经毒素产生。 DMF/MMF还d）诱导单核细胞抗氧化剂反应，E）抑制趋化性。此外，使用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编程宿主基因表达，以调节病毒扩散，炎症介质和凋亡的途径，这可以调节HIV/MDM Neurotoxin＆Neurotoxin生产和Neurotodgeneraserals和Neurotoxin＆Neurotoxin＆Neurotodgeneraserals and opoptosis。 由于DMF是可以口服的，CNS穿透性和微不足道的毒性，因此我们假设DMF可以是一种有效的神经保护剂，并且我们进一步假设转录组分析可以识别由DMF/MMF修饰的宿主途径，而DMF/MMF则是其神经保护性的构成的。我们将：1）定义DMF/MMF抑制HIV复制和MDM神经毒素通过HIV复制和TAT表达抑制的机制〜2）定义DMF/MMF对抑制单核细胞和巨噬细胞抑制单核和巨噬细胞激活的影响，通过抗氧化剂响应和其他途径〜3）确定DMF/MMF/MMF/MMFMF/MMF的机制〜3）迁移〜和4）确定DMF/MMF抑制单核细胞激活并诱导SIV感染的恒河猕猴中的抗氧化反应的能力。这应该为HIV患者的未来临床试验提供理由。