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

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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.

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Acknowledgements

The authors would like to thank Dr. De Camilli (Dept. of Neuroscience and Cell Biology, Yale University) for the gift of fibroblasts and Dr. Coate (Dept. of Biology, Georgetown University), for allowing us use of the Zeiss LSM880 microscope. The authors acknowledge Peter Johnson, imaging analysis manager at Georgetown University, for advice on quantitation of fluorescence images and Dr. Gu, Director of the Electron Microscopy Core at Houston Methodist Research Institute, for helping with MSN images.

This work was supported by US National Institute of Health grants R21-NS079172 and R01-NS074916. EW is supported by US National Institute of Health grant T32-NS041218. The work with nanoparticles was supported by the Brown Foundation (Project ID: 18130011) and by the Cullen Trust for Health Care Foundation (Project ID: 18130014).

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  1. Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Medical Center, EP09 New Research Building, 3970 Reservoir Rd, NW, Washington, DC, 20057, USA

    Erin D. Wenzel, Alessia Bachis, Valeria Avdoshina & Italo Mocchetti

  2. Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, 20057, USA

    Erin D. Wenzel

  3. Center for Biomimetic Medicine, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, 77030, USA

    Francesca Taraballi & Ennio Tasciotti

  4. Department of Orthopedics, Houston Methodist Hospital, Houston, TX, 77030, USA

    Ennio Tasciotti

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Correspondence to Italo Mocchetti.

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Wenzel, E.D., Bachis, A., Avdoshina, V. et al. Endocytic Trafficking of HIV gp120 is Mediated by Dynamin and Plays a Role in gp120 Neurotoxicity. J Neuroimmune Pharmacol 12, 492–503 (2017). https://doi.org/10.1007/s11481-017-9739-4

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