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

描述(申请人提供)：尽管使用了抗逆转录病毒疗法(ART)，但HIV相关的神经认知障碍(HAND)仍然很普遍，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特征。持续性全身炎症&单核细胞活化、中枢神经系统炎症、巨噬细胞活化与ART患者手相关。因此，虽然抗逆转录病毒治疗是艾滋病毒治疗的支柱，但迫切需要辅助疗法来抑制持续性炎症和病毒复制，并减轻手相关残疾的沉重负担。因此，从系统和中枢神经系统内抑制炎症和艾滋病毒复制的药物作为辅助神经保护剂特别有吸引力。我们建议进行一项双研究者MPI研究(Kolson，Aldvoni)，以调查一种新药富马酸二甲酯(DMF，Fumaderm(R))作为手部神经保护剂的候选药物，该药物目前正处于多发性硬化症的III期临床试验中。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)相关的炎症反应，以及c)单核细胞来源的巨噬细胞(MDM)的神经毒素产生。DMF/MMF还d)诱导单核细胞抗氧化反应，e)抑制趋化。此外，通过对HIV感染的T淋巴细胞和MDM的转录组分析，我们还证明了HIV以细胞依赖的方式重新编程宿主基因的表达，以调节病毒传播、炎症介质和细胞凋亡的途径，这些途径可以与HIV/MDM神经毒素产生和神经变性的途径相交。由于DMF是口服递送的，对中枢神经系统具有穿透性，毒性最小，我们假设DMF可以作为一种有效的神经保护剂，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)确定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)确定DMF/MMF通过抗氧化反应和其他途径抑制单核/巨噬细胞激活的作用；3)确定DMF/MMF调节单核细胞趋化和内皮迁移的机制；4)确定DMF/MMF抑制SIV感染猕猴单核细胞激活和诱导抗氧化反应的能力。这应该会为将来在HIV患者身上进行临床试验提供理论依据。 公共卫生相关性：尽管抗逆转录病毒疗法系统地抑制了艾滋病毒的复制，但艾滋病毒感染者的慢性炎症仍然存在。这种炎症可以推动疾病的发展，无论是在全身还是在中枢神经系统内。富马酸二甲酯(DMF)是一种安全有效的抗炎药物(在欧洲用于治疗牛皮癣)，对多发性硬化症患者具有中枢神经系统保护和抗炎作用。我们将通过研究确定它对HIV的潜在神经保护作用，这应该会导致在HIV患者中进行神经保护试验。

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.