Targeting Immunometabolism: a novel role for itaconate in the treatment of HIV-associated neurocognitive disorder and cocaine use disorder

HIV相关性神经认知障碍(HAND)是最常见和临床上最重要的疾病之一 艾滋病毒感染的并发症。迫切需要有效的治疗策略来治疗手部恶化 可卡因使用障碍(CUD)。通过对艾滋病毒诱导的转录组的广泛分析，我们 确定艾滋病毒和可卡因能深刻地诱导小胶质细胞特异性基因乌头酸酯的过度表达 脱羧酶1(Aod1)。Acod1将三羧酸(TCA)中间体顺乌头酸转化为衣康酸 在发炎期间。衣康酸激活抗炎转录因子从而保护巨噬细胞 感染引发的细胞死亡。尽管衣康酸的消炎作用已被鉴定为 在外周巨噬细胞中，免疫代谢的作用，包括衣康酸的产生，尚未被研究。 在艾滋病毒和可卡因暴露的小胶质细胞中。这一创新的提议将描述新的目标，以达到更好的效果。 在大脑里。这一建议的假设是衣康酸通过激活 HIV感染的小胶质细胞中的抗炎途径，从而减轻细胞死亡 从而使小胶质细胞HIV病毒储备库得以维持。此外，我们假设衣康酸的抑制作用 HIV感染的小胶质细胞的合成和下游途径具有选择性清除HIV的潜力 脑组织中的蓄水池--即一种创新的“非激活休克和杀死”治疗方法。相比之下，我们 还将探索细胞和血脑屏障(BBB)穿透的强大抗炎潜力 衣康酸的改性衍生物--衣康酸二甲酯和4-辛基衣康酸酯。我们的初步结果显示 4-辛基-衣康酸保护原代神经元免受艾滋病毒-TAT和可卡因的毒害。从而持续地激活 穿透血脑屏障的衣康酸衍生物的衣康酸途径可能是一种替代方法。 由CUD加重的手的治疗。这一创新的提案采用了一种新的方法，其核心是 在针对HIV感染的小胶质细胞时尚未考虑的免疫代谢。其他代谢物的酯， 包括富马酸，已经被批准用于牛皮癣和关节炎等炎症性疾病，正在增加 这些令人兴奋的研究的临床相关性。

HIV Associated Neurocognitive Disorder (HAND) is one of the most common and clinically important complications of HIV infection. There is an urgent need for effective therapeutic strategies for HAND exacerbated by Cocaine Use Disorder (CUD). Through an extensive analysis of the HIV-induced transcriptome, we determined that HIV and cocaine profoundly induce overexpression of the microglia-specific gene aconitate decarboxylase 1 (acod1). Acod1 converts the tricarboxylic acid (TCA) intermediate cis-aconitate to itaconate during inflammation. Itaconate activates anti-inflammatory transcription factors thereby protecting macrophages from infection-triggered cell death. Although the attenuation of inflammation by itaconate has been characterized in peripheral macrophages, the role of immunometabolism, including itaconate production, has not been studied in HIV and cocaine-exposed microglia. This innovative proposal will characterize novel targets of itaconate action in the brain. The hypothesis of this proposal is that itaconate balances neuroinflammation by activating anti-inflammatory pathways in HIV-infected microglia cells, consequently cell death is attenuated allowing microglial HIV reservoirs to be maintained. Further, we hypothesize that inhibition of itaconate synthesis and downstream pathways in HIV-infected microglia has the potential to selectively eliminate HIV reservoirs in the brain tissues – i.e., an innovative “Non-activating Shock and Kill” cure approach. In contrast, we will also explore the strong anti-inflammatory potential of the cell- and blood-brain barrier (BBB)-penetrating modified derivatives of itaconate -- dimethyl Itaconate (DMI) and 4-octyl-itaconate. Our preliminary results show that 4-octyl-itaconate protects primary neurons from HIV-tat and cocaine toxicity. Thus sustained activation of itaconate pathways by BBB-penetrable itaconate derivatives may be an alternative approach for the treatment of HAND worsened by CUD. This innovative proposal employs a novel approach centered on immunomeabolism that has not been considered in targeting HIV-infected microglia. Esters of other metabolites, including fumarate, are already approved for inflammatory diseases such as psoriasis and arthritis, increasing the clinical relevance of these exciting studies.