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Dopamine receptor activation increases HIV entry into primary human macrophages
Journal article   Open access   Peer reviewed

Dopamine receptor activation increases HIV entry into primary human macrophages

Peter J Gaskill, Hideaki H Yano, Ganjam V Kalpana, Jonathan A Javitch and Joan W Berman
PloS one, v 9(9), pp e108232-e108232
2014
DOI: https://doi.org/10.1371/journal.pone.0108232
PMID: 25268786
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0108232&type=printableView
Published, Version of Record (VoR) Open
url
https://doi.org/10.1371/journal.pone.0108232View
Published, Version of Record (VoR) Open

Abstract

Amides - pharmacology CCR5 Receptor Antagonists - pharmacology Dopamine - pharmacology Dopamine Antagonists - pharmacology Dose-Response Relationship, Drug Flupenthixol - pharmacology Gene Expression HIV Fusion Inhibitors - pharmacology HIV-1 - drug effects HIV-1 - physiology Humans Macrophages - drug effects Macrophages - metabolism Macrophages - virology Primary Cell Culture Quaternary Ammonium Compounds - pharmacology Receptors, CCR5 - genetics Receptors, CCR5 - metabolism Receptors, Dopamine D1 - genetics Receptors, Dopamine D1 - metabolism Receptors, Dopamine D2 - genetics Receptors, Dopamine D2 - metabolism Virus Internalization - drug effects
Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers.

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Collaboration types
Domestic collaboration
Web of Science research areas
Neurosciences
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