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

描述（由申请人提供）：尽管使用抗逆转录病毒治疗（ART）， HIV相关的神经认知障碍（HAND）仍然普遍存在，并且巨噬细胞/小胶质细胞中与HIV复制相关的中枢神经系统炎症和神经退行性变仍然是神经病理学特征。持续全身性炎症、单核细胞活化、中枢神经系统炎症、巨噬细胞活化与抗逆转录病毒治疗患者HAND相关。因此，尽管抗逆转录病毒治疗是HIV治疗的支柱，但迫切需要辅助治疗来抑制持续炎症和病毒复制，并减少HAND相关残疾的高负担。因此，在中枢神经系统和系统内抑制炎症和HIV复制的药物作为辅助神经保护剂特别有吸引力。我们正在提议一项双研究者MPI研究（Kolson, Aldvoni）来研究一种新药富马酸二甲酯（DMF，富马酸二甲酯(R)），目前正处于多发性硬化症的III期临床试验中)作为HAND的候选神经保护剂。通过我们的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)单核细胞源性巨噬细胞（MDM）神经毒素的产生。DMF/MMF也d)诱导单核细胞抗氧化反应和e)抑制趋化性。此外，通过对HIV感染的T淋巴细胞和MDM的转录组分析，我们还证明HIV以细胞依赖的方式重编程宿主基因表达，以调节病毒传播、炎症介质和细胞凋亡的途径，这些途径可能与HIV/MDM神经毒素产生和神经退行性变的途径交叉。由于DMF可口服，可穿透中枢神经系统，且毒性最小，我们假设DMF可能是HAND中有效的神经保护剂，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的基础。我们将:1)明确DMF/MMF通过HIV复制和Tat表达抑制HIV复制和MDM神经毒素产生的机制~ 2)明确DMF/MMF通过抗氧化反应等途径抑制单核细胞和巨噬细胞活化的作用~ 3)确定DMF/MMF调节单核细胞趋化和跨内皮迁移的机制~ 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。这将为未来在HIV患者中进行临床试验提供依据。

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. PUBLIC HEALTH RELEVANCE: Chronic inflammation persists in HIV-infected individuals despite systemic suppression of HIV replication by ART. Such inflammation can drive disease progression, both systemically and within the CNS. Dimethylfumarate (DMF) is a safe, effective anti- inflammatory drug (used in Europe to treat psoriasis) with CNS-protective, anti- inflammatory effects in multiple sclerosis patients. We will determine its potential neuroprotective use against HIV with investigations that should lead to a neuroprotection trial in HIV patients.