Dopamine receptor activation increases HIV entry into primary human macrophages

Peter J. Gaskill, Hideaki H. Yano, Ganjam V. Kalpana, Jonathan A. Javitch, Joan W. Berman

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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 dosedependent 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.

Original languageEnglish (US)
Article numbere108232
JournalPLoS One
Volume9
Issue number9
DOIs
StatePublished - Sep 30 2014

Fingerprint

Macrophages
Dopamine Receptors
dopamine
Dopamine
macrophages
Chemical activation
HIV
drug abuse
Street Drugs
Drug Users
drugs
Flupenthixol
Pharmaceutical Preparations
cocaine
Tropics
Central Nervous System Infections
Dopamine Antagonists
Methamphetamine
Neurology
neurotransmitters

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Dopamine receptor activation increases HIV entry into primary human macrophages. / Gaskill, Peter J.; Yano, Hideaki H.; Kalpana, Ganjam V.; Javitch, Jonathan A.; Berman, Joan W.

In: PLoS One, Vol. 9, No. 9, e108232, 30.09.2014.

Research output: Contribution to journalArticle

Gaskill, Peter J. ; Yano, Hideaki H. ; Kalpana, Ganjam V. ; Javitch, Jonathan A. ; Berman, Joan W. / Dopamine receptor activation increases HIV entry into primary human macrophages. In: PLoS One. 2014 ; Vol. 9, No. 9.
@article{eb5c8118cf454335b6bad2a1c4ebc952,
title = "Dopamine receptor activation increases HIV entry into primary human macrophages",
abstract = "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 dosedependent 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.",
author = "Gaskill, {Peter J.} and Yano, {Hideaki H.} and Kalpana, {Ganjam V.} and Javitch, {Jonathan A.} and Berman, {Joan W.}",
year = "2014",
month = "9",
day = "30",
doi = "10.1371/journal.pone.0108232",
language = "English (US)",
volume = "9",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "9",

}

TY - JOUR

T1 - Dopamine receptor activation increases HIV entry into primary human macrophages

AU - Gaskill, Peter J.

AU - Yano, Hideaki H.

AU - Kalpana, Ganjam V.

AU - Javitch, Jonathan A.

AU - Berman, Joan W.

PY - 2014/9/30

Y1 - 2014/9/30

N2 - 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 dosedependent 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.

AB - 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 dosedependent 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.

UR - http://www.scopus.com/inward/record.url?scp=84907510723&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907510723&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0108232

DO - 10.1371/journal.pone.0108232

M3 - Article

C2 - 25268786

AN - SCOPUS:84907510723

VL - 9

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 9

M1 - e108232

ER -