Synergistic effects of alcohol and HIV TAT protein on macrophage migration and neurotoxicity

Document Type

Article

Publication Date

7-15-2022

Abstract

The trans-activator of transcription (TAT) is a human immunodeficiency virus (HIV-1) regulatory protein that is actively sloughed by infected cells. Once released, TAT can injure bystander cells and bring about their dysfunction. In the presence of ethanol, TAT-induced toxicity potentiates and, in so doing, exacerbates inflammation. One key aspect of neuroinflammation involves the infiltration of peripheral macrophage to the central nervous system. Here, we use an interactive neuroimmune cell coculture of brain endothelial, astrocyte, neuron, and macrophage cells to model the blood-brain barrier and evaluate macrophage migration upon challenge with ethanol and TAT concentrations. We have limited this study to examine TAT concentrations found in people living with HIV-1 with (5 ng/mL) or without (25 ng/mL) viral suppression and ethanol doses below the legal driving limit (10 mM). In so doing, we study the effects of casual drinking on people living with HIV-1 but experiencing the best possible clinical outcome. We found that TAT alone increases macrophage migration between 0.5 and 4 h. while ethanol alone increases migration in a delayed manner (occurring at 48 h.). Ethanol-induced NO production by endothelial cells and TAT's chemoattractant properties may explain this dichotomy in migration pattern. Combined low dose ethanol significantly increased migration under both 5 ng/mL and 25 ng/mL TAT injuries across all timepoints. Our findings suggest that co-presence of ethanol and TAT may be the combination of an initial TAT effect followed by subsequent ethanol treatment. We also examined the structural and behavioral changes of neurons treated with TAT and ethanol to understand their contribution to neurotoxicity. The lowest concentration of TAT still induced neurotoxicity while alcohol potentiated neuronal death, even at low doses.

Identifier

85130417587 (Scopus)

Publication Title

Journal of Neuroimmunology

External Full Text Location

https://doi.org/10.1016/j.jneuroim.2022.577869

e-ISSN

18728421

ISSN

01655728

PubMed ID

35576691

Volume

368

Grant

R21AA028340

Fund Ref

National Institutes of Health

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