Presently, more than 40 millions people are infected with HIV-1, and AIDS is the fourth leading cause of death worldwide. The introduction of highly active antiretroviral therapy (HAART) has greatly reduced HIVmediated immunosuppression and mortality. However, it may not prevent neuronal damage associated with HIV-1 infection, and progressive damage to the Central Nervous System may be an emerging problem as AIDS patients live longer. Among the factors that have been shown to promote neuronal toxicity, the viral regulatory protein Tat has captured special attention. Tat protein is secreted by HIV-1 infected host cells and has been shown to enter bystander non-infected cells, including neurons. Recently, we have identified a new mechanism by which Tat can induce neuronal damage. It involves the binding of Tat to tubulin, recruitment of the ubiquitin-proteasome system to the proximity of microtubules, and degradation of microtubuleassociated protein 2 (MAP2), a critical component of the cytoskeleton. Immunohistochemical analysis of clinical samples from HIV-1 encephalopathy (HIVE) brain tissues demonstrated a predominantly cytoplasmic presence of Tat in neurons near microglial nodules, and loss of MAP2 in 70% of the affected neuronal cells. The observation that Tat can deregulate cytoskeletal factors led us to hypothesize that molecular events that depend on cytoskeletal integrity such as RNA trafficking could be also impaired. Our preliminary data confirm the ability of Tat to alter the expression of a subset of small RNAs, called microRNAs, which are known translational repressers. On the basis of these results, we will test the hypothesis that in neurons Tat can alter protein synthesis by modulating the activity of the cytoskeleton, the proteasome and the expression of microRNAs translational repressers. We expect that results from this study will critically redefine our knowledge of Tat-mediated neurotoxicity, and can provide potential targets for more effective therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH079751-06
Application #
8197513
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Joseph, Jeymohan
Project Start
2007-04-01
Project End
2013-03-31
Budget Start
2011-04-01
Budget End
2013-03-31
Support Year
6
Fiscal Year
2011
Total Cost
$271,547
Indirect Cost
Name
Louisiana State Univ Hsc New Orleans
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
Pacifici, Marco; Delbue, Serena; Kadri, Ferdous et al. (2014) Cerebrospinal fluid MicroRNA profiling using quantitative real time PCR. J Vis Exp :e51172
Pacifici, Marco; Delbue, Serena; Ferrante, Pasquale et al. (2013) Cerebrospinal fluid miRNA profile in HIV-encephalitis. J Cell Physiol 228:1070-5
Jeansonne, Duane; Pacifici, Marco; Lassak, Adam et al. (2013) Differential Effects of MicroRNAs on Glioblastoma Growth and Migration. Genes (Basel) 4:46-64
Pacifici, Marco; Peruzzi, Francesca (2012) Isolation and culture of rat embryonic neural cells: a quick protocol. J Vis Exp :e3965
Rom, Slava; Pacifici, Marco; Passiatore, Giovanni et al. (2011) HIV-1 Tat binds to SH3 domains: cellular and viral outcome of Tat/Grb2 interaction. Biochim Biophys Acta 1813:1836-44
Passiatore, Giovanni; Gentilella, Antonio; Rom, Slava et al. (2011) Induction of Id-1 by FGF-2 involves activity of EGR-1 and sensitizes neuroblastoma cells to cell death. J Cell Physiol 226:1763-70
Wilk, Anna; Urbanska, Katarzyna; Yang, Shuo et al. (2011) Insulin-like growth factor-I-forkhead box O transcription factor 3a counteracts high glucose/tumor necrosis factor-?-mediated neuronal damage: implications for human immunodeficiency virus encephalitis. J Neurosci Res 89:183-98
Rom, Slava; Rom, Inna; Passiatore, Giovanni et al. (2010) CCL8/MCP-2 is a target for mir-146a in HIV-1-infected human microglial cells. FASEB J 24:2292-300
Passiatore, Giovanni; Rom, Slava; Eletto, Davide et al. (2009) HIV-1 Tat C-terminus is cleaved by calpain 1: implication for Tat-mediated neurotoxicity. Biochim Biophys Acta 1793:378-87
Darbinian, Nune; Darbinyan, Armine; Czernik, Marta et al. (2008) HIV-1 Tat inhibits NGF-induced Egr-1 transcriptional activity and consequent p35 expression in neural cells. J Cell Physiol 216:128-34

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