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

总结 巨噬细胞在HIV-1感染的早期就被感染，并充当传播病毒的特洛伊木马 进入大脑众所周知，coconut可以加速HIV-1感染和这些细胞中的病毒产生， 提示加重疾病发病机制。此外，血管周围的巨噬细胞，小胶质细胞， 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。 有效的联合抗逆转录病毒疗法（cART）的情况。然而，不坚持抗逆转录病毒治疗 药物治疗和同时慢性可卡因滥用可导致这些潜伏的HIV-1重新激活， 感染的细胞和释放病毒毒素如达特等。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/神经认知功能障碍。 疾病（手）。代谢资源对HIV-1复制和维持潜伏期至关重要， 巨噬细胞由宿主提供。然而，HIV-1调节宿主代谢的机制 以及巨噬细胞中存活和复制的生物能量学仍然未知。我们的初步研究 证明HIV-1和可卡因劫持葡萄糖代谢途径以促进HIV-1复制， 巨噬细胞的存活和慢性可卡因重新激活潜伏感染者的病毒产生 单核细胞/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 （CNAC）和专门的核心（线粒体生理学和成像核心），我们将解剖 HIV-1调节宿主代谢和生物能量学以在宿主中存活和复制的机制。 巨噬细胞和小胶质细胞，以及慢性可卡因的影响。根据我们新的初步数据，我们 提出研究，以阐明参与调节表达/活性的分子机制， 可卡因和HIV-1对巨噬细胞和小胶质细胞中丙酮酸激酶2（PKM 2）的影响， HIV-1 LTR激活。此外，我们将描述参与摄取的分子机制。 葡萄糖和己糖激酶（HK）和葡萄糖-6-磷酸的表达/活性的调节 在单核细胞衍生的巨噬细胞（MDM）和小胶质细胞中， 可卡因和艾滋病毒感染者。此外，我们将评估可卡因对HIV-1复制的影响， MDM、小胶质细胞和HIV-1潜伏期U1模型中的存活率。这些研究是新颖的， 创新和解决HIV-1，可卡因和葡萄糖代谢之间的相互作用，这是一个领域， 被探索。预计该项目的结果将揭示病毒介导的新机制。 发病机制，并提供了新的途径，抗病毒治疗。 ¿

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. ¿