Approximately one-third of HIV-1 infected individuals develop HIV-1-associated neurocognitive disorders (HAND). Symptoms range from minor difficulties to severe neurodegenerative dementia and even with the advent of highly active antiretroviral therapy (HAART), while severe HIV-associated dementia is less common, minor cognitive motor disorders remains an important part of infection. The deleterious effects of opiates are complex and information regarding the actions of drugs of abuse on glial cell function is very limited though they are known to be critical to opiate response. Moreover, the consequent effects of the actions of drugs of abuse and the manifestation of substance abuse on neuronal function are not well known. The proposed project will investigate the role of autophagy in microglia-induced neuroAIDS in the context of substance abuse. The three correlated specific aims are directed at: 1) identifying a novel mechanism in the biology of microglia that regulates HIV-1 replication and whether morphine converges on HIV-1 infection through this pathway~ 2) characterization at cellular levels the consequences of HIV-1 induced lysosomal dysfunction and whether prior and/ or concurrent substance abuse modifies cell function~ 3) examining the signaling pathways and the significance (protective vs. toxic) of the autophagy process activated by HIV-1 and morphine in microglia cells and neurons. Dr. El-Hage has the expertise, leadership, and motivation necessary to run a successful research program and the purpose of getting this award is to enable Dr. El-Hage to become an independent scientist.

Public Health Relevance

The goals of this proposal are twofold~ (i) to study the consequences underlying HIV-1 and morphine deregulation of autophagy on microglia cell function, and (b) to determine whether autophagy plays a protective role or instead contributes to pathogenic neuronal cell death exposed to HIV-1 and substance abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA036154-02
Application #
8701265
Study Section
Special Emphasis Panel (ZDA1-GXM-A (08))
Program Officer
Satterlee, John S
Project Start
2013-07-15
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$381,250
Indirect Cost
$131,250
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Dever, Seth M; Rodriguez, Myosotys; El-Hage, Nazira (2016) β-Adrenergic receptor gene expression in HIV-associated neurocognitive impairment and encephalitis: implications for MOR-1K subcellular localization. J Neurovirol 22:866-870
Kaushik, Ajeet; Jayant, Rahul D; Nikkhah-Moshaie, Roozbeh et al. (2016) Magnetically guided central nervous system delivery and toxicity evaluation of magneto-electric nanocarriers. Sci Rep 6:25309
Rodriguez, Myosotys; Kaushik, Ajeet; Lapierre, Jessica et al. (2016) Electro-Magnetic Nano-Particle Bound Beclin1 siRNA Crosses the Blood-Brain Barrier to Attenuate the Inflammatory Effects of HIV-1 Infection in Vitro. J Neuroimmune Pharmacol :
Dever, Seth M; Rodriguez, Myosotys; Lapierre, Jessica et al. (2015) Differing roles of autophagy in HIV-associated neurocognitive impairment and encephalitis with implications for morphine co-exposure. Front Microbiol 6:653
Xu, Ruqiang; El-Hage, Nazira; Dever, Seth M (2015) Fluorescently-labeled RNA packaging into HIV-1 particles: Direct examination of infectivity across central nervous system cell types. J Virol Methods 224:20-9
El-Hage, Nazira; Rodriguez, Myosotys; Dever, Seth M et al. (2015) HIV-1 and morphine regulation of autophagy in microglia: limited interactions in the context of HIV-1 infection and opioid abuse. J Virol 89:1024-35
Masvekar, Ruturaj R; El-Hage, Nazira; Hauser, Kurt F et al. (2015) GSK3β-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
El-Hage, Nazira; Rodriguez, Myosotys; Podhaizer, Elizabeth M et al. (2014) Ibudilast (AV411), and its AV1013 analog, reduce HIV-1 replication and neuronal death induced by HIV-1 and morphine. AIDS 28:1409-19