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

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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. �