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Exosome-associated release, uptake, and neurotoxicity of HIV-1 Tat protein

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Abstract

HIV-1 Tat is an indispensible transactivator for HIV gene transcription and replication. It has been shown to exit cells as a free protein and enter neighboring cells or interact with surface receptors of neighboring cells to regulate gene expression and cell function. In this study, we report, for the first time, exosome-associated Tat release and uptake. Using a HIV-1 LTR-driven luciferase reporter-based cell assay and Western blotting or in combination with exosome inhibitor, OptiPrep gradient fractionation, and exosome depletion, we demonstrated significant presence of HIV-1 Tat in exosomes derived from Tat-expressing primary astrocytes, Tat-transfected U373.MG and 293T, and HIV-infected MT4. We further showed that exosome-associated Tat from Tat-expressing astrocytes was capable of causing neurite shortening and neuron death, further supporting that this new form of extracellular Tat is biologically active. Lastly, we constructed a Tat mutant deleted of its basic domain and determined the role of the basic domain in Tat trafficking into exosomes. Basic domain-deleted Tat exhibited no apparent effects on Tat trafficking into exosomes, while maintained its dominant-negative function in Tat-mediated LTR transactivation. Taken together, these results show a significant fraction of Tat is secreted and present in the form of exosomes and may contribute to the stability of extracellular Tat and broaden the spectrum of its target cells.

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Acknowledgments

This work was supported in part by the grants NIH/NINDS R01NS094108 and NIH/NIMH R01MH092673 (to JJH) and T32AG20494 (to PR, PI: Dr. Meharvan Singh) from the National Institutes of Health.

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  1. Department of Cell Biology and Immunology, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA

    Pejman Rahimian & Johnny J. He

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Rahimian, P., He, J.J. Exosome-associated release, uptake, and neurotoxicity of HIV-1 Tat protein. J. Neurovirol. 22, 774–788 (2016). https://doi.org/10.1007/s13365-016-0451-6

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