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HIV-1 Tat and Cocaine Impair Survival of Cultured Primary Neuronal Cells via a Mitochondrial Pathway

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Abstract

Addictive stimulant drugs, such as cocaine, are known to increase the risk of exposure to HIV-1 infection and hence predispose towards the development of AIDS. Previous findings suggested that the combined effect of chronic cocaine administration and HIV-1 infection enhances cell death. Neuronal survival is highly dependent on the health of mitochondria providing a rationale for assessing mitochondrial integrity and functionality following cocaine treatment, either alone or in combination with the HIV-1 viral protein Tat, by monitoring ATP release and mitochondrial membrane potential (ΔΨm). Our results indicate that exposing human and rat primary hippocampal neurons to cocaine and HIV-1 Tat synergistically decreased both mitochondrial membrane potential and ATP production. Additionally, since previous studies suggested HIV-1 infection alters autophagy in the CNS, we investigated how HIV-1 Tat and cocaine affect autophagy in neurons. The results indicated that Tat induces an increase in LC3-II levels and the formation of Parkin-ring-like structures surrounding damaged mitochondria, indicating the possible involvement of the Parkin/PINK1/DJ-1 (PPD) complex in neuronal degeneration. The importance of mitochondrial damage is also indicated by reductions in mitochondrial membrane potential and ATP content induced by HIV-1 Tat and cocaine.

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Acknowledgements

We thank Dr. Manish Gupta and other past and present members of the Department of Neuroscience and Center for Neurovirology for their insightful discussion and sharing of ideas and reagents. This study utilized services offered by Lewis Katz School of Medicine Comprehensive NeuroAIDS Center at Temple University. This work was supported by grants P01 DA037830 and P30 MH092177 awarded to KK.

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Author notes

  1. Francesca Isabella De Simone & Nune Darbinian

    Present address: Shriners Hospitals Pediatric Research Center, 3500 N. Broad Street, Philadelphia, PA, 19140, USA

Authors and Affiliations

  1. Department of Neuroscience, Center for Neurovirology and Comprehensive NeuroAIDS Center, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA

    Francesca Isabella De Simone, Nune Darbinian, Shohreh Amini, Martyn K. White, Prasun K. Datta, Dianne Langford & Kamel Khalili

  2. Department of Biology, College of Science and Technology, Temple University, 1803 N. Broad Street, Philadelphia, PA, 19122, USA

    Shohreh Amini

  3. Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA, 19140, USA

    Madesh Muniswamy & John W. Elrod

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  1. Francesca Isabella De Simone
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Corresponding author

Correspondence to Kamel Khalili.

Ethics declarations

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All studies were reviewed and approved by the Katz School of Medicine IACUC.

No human subjects were used in these studies.

Funding

This study was funded by grant number P01DA037830 and P30MH092177 awarded to K. Khalili by NIH.

Conflict of Interest

F.I. De Simone declares that she has no conflict of interest.

N. Darbinian declares that she has no conflict of interest.

S. Amini declares that she has no conflict of interest.

M.K. White declares that he has no conflict of interest.

J. Elrod declares that he has no conflict of interest.

P. Datta declares that he has no conflict of interest.

D. Langford declares that she has no conflict of interest.

K. Khalili declares that he has no conflict of interest.

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De Simone, F.I., Darbinian, N., Amini, S. et al. HIV-1 Tat and Cocaine Impair Survival of Cultured Primary Neuronal Cells via a Mitochondrial Pathway. J Neuroimmune Pharmacol 11, 358–368 (2016). https://doi.org/10.1007/s11481-016-9669-6

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  • DOI: https://doi.org/10.1007/s11481-016-9669-6

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