Project 1 Reciprocal interaction of cocaine and HIV-1 on glycolytic pathways in macrophages and microglia cells

摘要 巨噬细胞在HIV-1感染早期被感染，并充当传播病毒的特洛伊木马 进入大脑。众所周知，可卡因会加速这些细胞中艾滋病毒-1的感染和病毒的产生，并已被 提示加重疾病发病机制。此外，血管周围巨噬细胞、小胶质细胞和 在一定程度上，星形胶质细胞也是目前潜伏的HIV-1的建立和维持的场所 有效联合抗逆转录病毒治疗(CART)的情景。然而，不坚持抗逆转录病毒治疗 药物治疗和同时长期滥用可卡因可导致这些人体内HIV-1潜伏地重新激活 感染的细胞和释放的病毒毒素，如TAT和其他。这些病毒毒素与慢性 可卡因可以扰乱脑细胞的稳态，从而导致HIV-1相关的神经/神经认知 精神障碍(手)。对HIV-1复制和维持潜伏期至关重要的代谢资源 巨噬细胞由宿主提供。然而，HIV-1调节宿主新陈代谢的机制 而在巨噬细胞中生存和复制的生物能量学仍然未知。我们的初步研究 证明HIV-1和可卡因劫持了葡萄糖代谢途径以促进HIV-1的复制和 巨噬细胞存活和慢性可卡因重新激活潜伏感染患者的病毒生成 单核/巨噬细胞。在本计划项目的背景下，通过利用专业知识和基础设施 由药物滥用研究中心(CSAR)和综合神经艾滋病中心提供 和专门的核心(线粒体生理学和成像核心)，我们将剖析 HIV-1调节宿主新陈代谢和生物能量学在体内存活和复制的机制 巨噬细胞和小胶质细胞，以及慢性可卡因的影响。基于我们新的初步数据，我们 建议进行研究，以阐明参与调控蛋白表达/活性的分子机制(S) 可卡因和HIV-1对巨噬细胞和小胶质细胞中的丙酮酸激酶2型(PKM2)的影响 HIV-1 LTR激活。此外，我们将描述参与摄取的分子机制(S)。 葡萄糖与己糖激酶(HK)和葡萄糖-6-磷酸的表达/活性调节 慢性染毒对单核巨噬细胞和小胶质细胞脱氢酶(G6PD)的影响 可卡因和感染了HIV-1病毒。此外，我们将评估可卡因对艾滋病毒-1复制和 在MDM、小胶质细胞和HIV-1潜伏期的U1模型中存活。这些研究是新颖的和高度的 创新并解决HIV-1、可卡因和葡萄糖代谢之间的相互作用这一领域尚未 被探索。预计该项目的结果将揭开与病毒有关的新机制。 并为抗病毒治疗提供了新的途径。 �

SUMMARY Macrophages are infected early in HIV-1 infection and act as Trojan horses for dissemination of the virus into the brain. Cocaine is known to accelerate HIV-1 infection and virus production in these cells and has been suggested to exacerbate disease pathogenesis. Furthermore, perivascular macrophages, microglia and, to a limited degree, astrocytes are also sites for establishment and maintenance of latent HIV-1 in the current scenario of effective combined antiretroviral therapy (cART). However, non-adherence to antiretroviral medication and simultaneous chronic cocaine abuse can lead to the reactivation of HIV-1 in these latently infected cells and release of virotoxins such as Tat and others. These virotoxins in combination with chronic cocaine can perturb brain cell homeostasis thereby leading to HIV-1 associated neurological/neurocognitive disorders (HAND). The metabolic resources crucial for HIV-1 replication and maintaining latency in macrophages are provided by the host. However, the mechanisms by which HIV-1 modulates host metabolism and bioenergetics for survival and replication in macrophages remain unknown. Our preliminary studies demonstrate that HIV-1 and cocaine hijacks the glucose metabolism pathway to facilitate HIV-1 replication and survival in macrophages and chronic cocaine reactivates virus production in latently infected monocyte/macrophages. In context of this program project by leveraging on the expertise and infrastructure provided by the Center for Substance Abuse Research (CSAR) and Comprehensive NeuroAIDS Center (CNAC), and the specialized core (Mitochondrial Physiology and Imaging Core) we will dissect the mechanisms by which HIV-1 modulates host metabolism and bioenergetics for survival and replication in macrophages and microglia, and the impact of chronic cocaine. Based on our novel preliminary data, we propose studies to elucidate the molecular mechanism(s) involved in the modulation of expression/activity of pyruvate kinase muscle type 2 (PKM2) by cocaine and HIV-1 in macrophages and microglia, and its impact on HIV-1 LTR activation. In addition, we will characterize the molecular mechanism(s) involved in the uptake of glucose and the modulation of expression/activity of hexokinase (HK) and glucose-6-phosphate dehydrogenase (G6PD) in monocyte derived macrophages (MDMs) and microglia chronically treated with cocaine and infected with HIV-1. Moreover, we will assess the impact of cocaine on HIV-1 replication and survival in MDMs, microglia and in the U1 model of HIV-1 latency. These studies are novel and highly innovative and address the cross-talk between HIV-1, cocaine and glucose metabolism an area which is yet to be explored. It is expected that the outcome of this project unravels novel mechanisms involved in viral pathogenesis and offer novel avenues for antiviral therapy. �