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。目前迫切需要有效的治疗策略， 使用障碍（CUD）。通过对HIV诱导的转录组的广泛分析，我们 确定HIV和可卡因深刻地诱导小胶质细胞特异性基因aconitate的过度表达 脱羧酶1（acod 1）。Acod 1将三羧酸（TCA）中间体顺乌头酸转化为衣康酸 在炎症期间。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虽然衣康酸盐减轻炎症的特点是 在外周巨噬细胞中，免疫代谢的作用，包括衣康酸盐的产生，还没有被研究过 艾滋病病毒和可卡因暴露的小胶质细胞。这一创新性的建议将表征衣康酸作用的新靶点 在大脑中。这一提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，因此细胞死亡减弱 从而维持小胶质细胞HIV库。此外，我们假设抑制衣康酸 HIV感染的小胶质细胞中的合成和下游途径具有选择性消除HIV的潜力 脑组织中的储库-即，一种创新的“非激活性休克和杀死”治疗方法。相反，我们 还将探索细胞和血脑屏障（BBB）穿透的强大抗炎潜力， 衣康酸酯的改性衍生物--衣康酸二甲酯（DMC）和衣康酸4-辛酯。我们的初步结果表明 4-辛基衣康酸酯保护初级神经元免受HIV-tat和可卡因毒性的影响。因此，持续激活 通过BBB-可穿透的衣康酸衍生物的衣康酸途径可能是治疗糖尿病的替代方法。 治疗HAND因CUD而恶化。这一创新提案采用了一种新颖的方法， 在靶向HIV感染的小胶质细胞方面，尚未考虑免疫微球蛋白。其他代谢物的酯， 包括富马酸盐，已经被批准用于炎症性疾病，如牛皮癣和关节炎， 这些激动人心的研究的临床意义。

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.