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.
Methamphetamine is a drug that is often abused in the HIV+ population. It leads to risky behavior that increases the chances for HIV infection. Once HIV infected, Meth abusers have worse neurocognitive impairment than HIV+ non Meth abusers. We propose to study mechanisms at the cellular and molecular level to understand how Meth and HIV lead to worse clinical outcome than either factor alone. Understanding these pathways is a critical first step to devise novel strategies to treat this co-morbid condition.
|Khodr, Christina E; Chen, Lihua; Dave, Sonya et al. (2016) Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons. Neurobiol Dis 94:85-94|
|Lutgen, Victoria; Narasipura, Srinivas D; Sharma, Amit et al. (2016) Î²-Catenin signaling positively regulates glutamate uptake and metabolism in astrocytes. J Neuroinflammation 13:242|
|Aljawai, Yosra; Richards, Maureen H; Seaton, Melanie S et al. (2014) Î²-Catenin/TCF-4 signaling regulates susceptibility of macrophages and resistance of monocytes to HIV-1 productive infection. Curr HIV Res 12:164-73|
|Henderson, Lisa J; Sharma, Amit; Monaco, Maria Chiara G et al. (2012) Human immunodeficiency virus type 1 (HIV-1) transactivator of transcription through its intact core and cysteine-rich domains inhibits Wnt/Ã½Ã½-catenin signaling in astrocytes: relevance to HIV neuropathogenesis. J Neurosci 32:16306-13|
|Al-Harthi, Lena (2012) Wnt/Î²-catenin and its diverse physiological cell signaling pathways in neurodegenerative and neuropsychiatric disorders. J Neuroimmune Pharmacol 7:725-30|
|Al-Harthi, Lena (2012) Interplay between Wnt/Î²-catenin signaling and HIV: virologic and biologic consequences in the CNS. J Neuroimmune Pharmacol 7:731-9|
|Li, Wei; Henderson, Lisa J; Major, Eugene O et al. (2011) IFN-gamma mediates enhancement of HIV replication in astrocytes by inducing an antagonist of the beta-catenin pathway (DKK1) in a STAT 3-dependent manner. J Immunol 186:6771-8|