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Adenosine Triphosphate Released from HIV-Infected Macrophages Regulates Glutamatergic Tone and Dendritic Spine Density on Neurons

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Abstract

Despite wide spread use of combination antiretroviral therapy (cART) in developed countries, approximately half of HIV-infected patients will develop impairments in cognitive function. Accumulating evidence suggests that neuronal dysfunction can be precipitated by HIV-infection of macrophages by mechanisms that involve alterations in innate and adaptive immune responses. HIV-infection of macrophages is known to increase the release of soluble neurotoxins. However, the composition of products released from infected macrophages is complex and not fully known. In this study we provide evidence that ATP and other immuno-/neuromodulatory nucleotides are exported from HIV-infected macrophages and modify neuronal structure. Supernatants collected from HIV-infected macrophages (HIV/MDM) contained large amounts of ATP, ADP, AMP and small amounts of adenosine, in addition to glutamate. Dilutions of these supernatants that were sub-threshold for glutamate receptor activation evoked rapid calcium flux in neurons that were completely inhibited by the enzymatic degradation of ATP, or by blockade of calcium permeable purinergic receptors. Applications of these highly diluted HIV/MDM onto neuronal cultures increased the amount of extracellular glutamate by mechanisms dependent on purinergic receptor activation, and downregulated spine density on neurons by mechanisms dependent on purinergic and glutamate receptor activation. We conclude from these data that ATP released from HIV-infected macrophages downregulates dendritic spine density on neurons by a mechanism that involves purinergic receptor mediated modulation of glutamatergic tone. These data suggest that neuronal function may be depressed in HIV infected individuals by mechanisms that involve macrophage release of ATP that triggers secondary effects on glutamate handling.

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Abbreviations

5-BDBD:

5-(3-bromophenyl)-1,3-dihydro-2H-benzofuro[3,2-e]-1,4-diazepin-2-one

ADP:

adenosine diphosphate

AMP:

adenosine monophosphate

AMPA:

α-amino-3-hydroxy-5-methyl-isoxazol-4-yl propionate

ATP:

adenosine triphosphate

AZ10606120:

N-[2-[[2-[(2-Hydroxyethyl)amino]ethyl]amino]-5-quinolinyl]-2-tricyclo[3.3.1.13,7]dec-1-ylacetamide dihydrochloride

cART:

combination antiretroviral therapy

DIV:

days in vitro

DL-TBOA:

DL-threo-β-Benzyloxyaspartic acid

ECNI:

electron capture negative ionization

GC:

gas chromatography

HAND:

HIV-associated neurocognitive disorder

HIV:

human immunodeficiency virus

HIV/MDM:

HIV-infected monocyte derived macrophage

MDM:

monocyte derived macrophage

MK-801:

5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate

MS:

mass spectrometry

NBQX:

2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide

NMDA:

N-methyl-D-aspartate

PBS:

phosphate-buffered saline

PPADS:

pyridoxal phosphate-6-azophenyl-2'-4'-disulphonic acid

TBS:

tris-buffered saline

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Acknowledgments

The authors would like to acknowledge Carrie Berlett for her technical support. This study was supported by NIH grants AA0017408, MH077542 and AG034849 to NJH.

Competing interests

The authors have no conflicts of interest or competing interests to disclose.

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Authors and Affiliations

  1. Department of Neurology, Richard T. Johnson Division of Neuroimmunology and Neurological Infections, Johns Hopkins University School of Medicine, Pathology 517, 600 North Wolfe Street, Baltimore, MD, 21287, USA

    Luis B. Tovar-y-Romo, Veera Venkata Ratnam Bandaru & Norman J. Haughey

  2. Department of Neurology, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA

    Dennis L. Kolson

  3. Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Julia L. Drewes & David R. Graham

Authors
  1. Luis B. Tovar-y-Romo
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  2. Dennis L. Kolson
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  3. Veera Venkata Ratnam Bandaru
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  4. Julia L. Drewes
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  5. David R. Graham
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  6. Norman J. Haughey
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Correspondence to Norman J. Haughey.

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Tovar-y-Romo, L.B., Kolson, D.L., Bandaru, V.V.R. et al. Adenosine Triphosphate Released from HIV-Infected Macrophages Regulates Glutamatergic Tone and Dendritic Spine Density on Neurons. J Neuroimmune Pharmacol 8, 998–1009 (2013). https://doi.org/10.1007/s11481-013-9471-7

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  • DOI: https://doi.org/10.1007/s11481-013-9471-7

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