mechanisms of HIV and drug abuse pathogenesis in CNS

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DESCRIPTION (provided by applicant): Methamphetamine (Meth) is a psychostimulant that has exceeded cocaine use in the US. Drug abuse in general and Meth use in particular is a risk factor for HIV acquisition and disease progression. Meth enhances HIV/SIV viral load and exacerbates HIV associated neurocognitive disorders (HAND). The cellular and molecular mechanisms by which Meth leads to heightened pathogenesis in the CNS are not entirely clear. While a number of studies have directly assessed the impact of Meth and HIV viral toxins in neurons, the role of astrocytes, which make up to 70% of cells in the CNS and perform vital functions to maintain CNS homeostasis, is understudied in Meth/HIV co-morbidity. We demonstrate that Meth induces HIV replication in astrocytes, inhibits -catenin signaling, and leads to dysregulation in the glutamate transport network. Meth-mediated inhibition of -catenin signaling is particularly important because this pathway is critical for cell-to-cell communication survival, proliferation, and we show that it regulates Excitatory Amino Acid Transporter 2 (EAAT2), the predominate glutamate transporter responsible for ~90% of glutamate uptake by astrocytes. This application will focus on the virology, function, and potential therapeutics in th axis between Meth and -catenin signaling in Meth/HIV co-morbidity. Specifically, we propose to identify the mechanism by which Meth induces HIV productive replication (Aim 1/virology); determine the impact of Meth/ -catenin axis on the function of astrocytes (Aim 2/function); and assess the ability of small molecule modulators of the -catenin pathway to overcome Meth effects on HIV and function of astrocytes (Aim 3/therapeutics). Collectively, these studies will provide novel mechanistic insights into HIV/Meth co-morbidity and expedite the development of pharmacotherpies that can target Meth and HIV exacerbated neuropathogenesis by targeting the cellular protective properties of the -catenin pathway.