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J Neuroimmune Pharmacol. 2017 Sep;12(3):492-503. doi: 10.1007/s11481-017-9739-4. Epub 2017 Mar 27.

Endocytic Trafficking of HIV gp120 is Mediated by Dynamin and Plays a Role in gp120 Neurotoxicity.

Author information

1
Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Medical Center, EP09 New Research Building, 3970 Reservoir Rd, NW, Washington, DC, 20057, USA.
2
Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, 20057, USA.
3
Center for Biomimetic Medicine, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, 77030, USA.
4
Department of Orthopedics, Houston Methodist Hospital, Houston, TX, 77030, USA.
5
Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Medical Center, EP09 New Research Building, 3970 Reservoir Rd, NW, Washington, DC, 20057, USA. moccheti@georgetown.edu.

Abstract

Neurons that endocytose the human immunodeficiency virus-1 (HIV) protein gp120 exhibit neurite retraction and activation of caspase-3, suggesting that the endocytic process may be crucial for gp120-mediated neuronal injury. The goal of this study is to demonstrate that internalization and accumulation of gp120 play a role in its neurotoxic effects. In mammalian cells, endocytosis is primarily a dynamin-dependent process. To establish whether gp120 is endocytosed in a dynamin-dependent manner, we used fibroblasts in which deletion of dynamins was induced by tamoxifen. We observed a robust reduction of intracellular gp120 immunoreactivity in tamoxifen-treated cells. To examine whether endocytosis of gp120 is crucial for its neurotoxic effect, we blocked gp120 internalization into primary rat cortical neurons by dynasore, an inhibitor of the dynamin GTP-ase activity. We found that dynasore blocks both gp120 internalization and neurotoxicity. We then utilized gp120-loaded mesoporous silica nanoparticles to deliver gp120 intracellularly. We established that once internalized, gp120 is neurotoxic regardless of chemokine receptor activation. Our data suggest that dynamin-dependent endocytosis of gp120 is critical for its neurotoxicity.

KEYWORDS:

CXCR4; Dynasore; Mesoporous silica nanoparticles; Tat; pErk

PMID:
28349243
PMCID:
PMC5815508
DOI:
10.1007/s11481-017-9739-4
[Indexed for MEDLINE]
Free PMC Article

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