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），但HIV相关神经认知障碍（HAND）仍然普遍存在，与巨噬细胞/小胶质细胞中HIV复制相关的CNS炎症和神经变性仍然是神经病理学特征。 持续的全身性炎症和单核细胞活化、CNS炎症、巨噬细胞活化与接受ART的患者中的HAND相关。因此，尽管ART是HIV治疗的支柱，但迫切需要连续性治疗来抑制持续性炎症和病毒复制，并降低HAND相关残疾的高负担。 因此，全身性和CNS内抑制炎症和HIV复制的药物作为连续性神经保护剂特别有吸引力。 我们提出了一项双研究者MPI研究（Kolson，Aldvoni），以研究一种新药富马酸二甲酯（DMF，Fumaderm（R），目前正在进行多发性硬化症的III期临床试验）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及其主要体内代谢产物MMF可抑制a）HIV复制，B）相关炎症反应和c）单核细胞衍生巨噬细胞（MDM）中的神经毒素产生。 DMF/MMF还d）诱导单核细胞抗氧化反应和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，我们还证明了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，这可以交叉HIV/MDM神经毒素产生和神经变性的途径。 由于DMF可口服给药，具有CNS渗透性，毒性极低，因此我们假设DMF可以成为HAND中的有效神经保护剂，我们进一步假设转录组分析可以识别DMF/MMF修饰的宿主途径，这些途径是其神经保护作用的基础。我们将：1）确定DMF/MMF抑制HIV复制和通过HIV复制和达特表达产生MDM神经毒素的机制~ 2）确定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调节单核细胞趋化性和巨噬细胞活化的机制。跨内皮迁移和4）确定DMF/MMF抑制单核细胞活化和诱导SIV感染恒河猴抗氧化反应的能力。这将为未来在HIV患者中进行临床试验提供理论依据。 公共卫生相关性：尽管ART系统性抑制HIV复制，但HIV感染者的慢性炎症持续存在。这种炎症可驱动疾病进展，包括系统性和CNS内。富马酸二甲酯（DMF）是一种安全、有效的抗炎药物（在欧洲用于治疗银屑病），在多发性硬化症患者中具有CNS保护性抗炎作用。 我们将通过调查确定其对HIV的潜在神经保护作用，这些调查应导致在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.