The neurotoxic consequences of opiate drug and HIV-1 interactions on striatal neurons and on the underlying intracellular signaling pathways (autophagy, ER-stress/unfolded protein responses (UPR), apoptosis) resulting in sublethal injury and death will be explored. Accumulating evidence indicates that opioid drug abuse per se directly exacerbates the neuropathology of HIV-1. We have found that (1) opioid drugs exacerbate neuronal injury and death through independent actions on ?-opioid receptor (MOR) expressing neurons, astroglia and microglia;and (2) that neuronal death is preceded by non-lethal changes in synaptodendritic pathology that are presumably reversible. Opiate abuse potentiates the neuropathogenesis of HIV largely/exclusively by synergistically disrupting glial function and dendritic pathology. We hypothesize that opioid-HIV interactive increases in neuron death are preceded by cumulative insults to synaptic organization and function that originate in glia, are non-lethal, and assumed reversible. These reductions in neuronal function likely underlie cognitive impairment in neuroAIDS and represent an important therapeutic target for chronic drug abuse-HIV comorbidity.
Aim 1 will examine opioid and HIV-1-dependent (Tat, gp120, and live virus) sublethal neuronal dysfunction and/or death as a continuum using multiple in vitro models including primary human dissociated neuron, astroglia, and microglial cultures. It is likely that apoptosis, autophagy, and ER-stress/UPR are operative in sublethal injury as well as during neuron death, and these pathways are evaluated and tested for potentially reversible effects.
Aim 2 will identify the extent to which apoptotic, autophagic, and ER-stress/UPR events are associated with opiate-HIV-induced neuronal dysfunction and/or death in vivo. Our ability to visualize/manipulate apoptotic, autophagic, and UPR events in living, cultured neurons will garner new insight into the pathogenesis of opioid abuse/HIV comorbidity and will reveal novel strategies to reverse neuron injury. Our labs were the first to show that opioids, in large part via glial intermediates, exacerbate HIV-induced CNS neuroimmune responses and neuronal injury. Our long-term goal is to define the mechanisms by which opiate drug use or abuse contributes to neurodegeneration accompanying HIVE, and to identify signaling pathways that could be targeted for therapeutic intervention.

Public Health Relevance

This grant tests the innovative concept that chronic opiate abuse and HIV injure neurons and brain circuitry through the competing actions of three interrelated cell stress pathways (apoptotic, autophagic, and ER-stress). We will test whether experimentally manipulating each of these pathways can prevent the types of neuronal injury associated with neurocognitive deficits occurring with drug abuse and/or neuroAIDS.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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NeuroAIDS and other End-Organ Diseases Study Section (NAED)
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Sorensen, Roger
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Virginia Commonwealth University
Schools of Medicine
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Gonek, Maciej; McLane, Virginia D; Stevens, David L et al. (2018) CCR5 mediates HIV-1 Tat-induced neuroinflammation and influences morphine tolerance, dependence, and reward. Brain Behav Immun 69:124-138
Leibrand, Crystal R; Paris, Jason J; Ghandour, M Said et al. (2017) HIV-1 Tat disrupts blood-brain barrier integrity and increases phagocytic perivascular macrophages and microglia in the dorsal striatum of transgenic mice. Neurosci Lett 640:136-143
Schier, Christina J; Marks, William D; Paris, Jason J et al. (2017) Selective Vulnerability of Striatal D2 versus D1 Dopamine Receptor-Expressing Medium Spiny Neurons in HIV-1 Tat Transgenic Male Mice. J Neurosci 37:5758-5769
Marks, William D; Paris, Jason J; Schier, Christina J et al. (2016) HIV-1 Tat causes cognitive deficits and selective loss of parvalbumin, somatostatin, and neuronal nitric oxide synthase expressing hippocampal CA1 interneuron subpopulations. J Neurovirol 22:747-762
Fitting, Sylvia; Stevens, David L; Khan, Fayez A et al. (2016) Morphine Tolerance and Physical Dependence Are Altered in Conditional HIV-1 Tat Transgenic Mice. J Pharmacol Exp Ther 356:96-105
Paris, Jason J; Zou, ShiPing; Hahn, Yun K et al. (2016) 5?-reduced progestogens ameliorate mood-related behavioral pathology, neurotoxicity, and microgliosis associated with exposure to HIV-1 Tat. Brain Behav Immun 55:202-214
Sahu, Geetaram; Farley, Kalamo; El-Hage, Nazira et al. (2015) Cocaine promotes both initiation and elongation phase of HIV-1 transcription by activating NF-?B and MSK1 and inducing selective epigenetic modifications at HIV-1 LTR. Virology 483:185-202
Masvekar, Ruturaj R; El-Hage, Nazira; Hauser, Kurt F et al. (2015) GSK3?-activation is a point of convergence for HIV-1 and opiate-mediated interactive neurotoxicity. Mol Cell Neurosci 65:11-20
Masvekar, Ruturaj R; El-Hage, Nazira; Hauser, Kurt F et al. (2014) Morphine enhances HIV-1SF162-mediated neuron death and delays recovery of injured neurites. PLoS One 9:e100196
Dever, Seth M; Costin, Blair N; Xu, Ruqiang et al. (2014) Differential expression of the alternatively spliced OPRM1 isoform ?-opioid receptor-1K in HIV-infected individuals. AIDS 28:19-30

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