TY - JOUR
T1 - Human immunodeficiency virus (HIV) infection of human macrophages is increased by dopamine
T2 - A bridge between HIV-associated neurologic disorders and drug abuse
AU - Gaskill, Peter J.
AU - Calderon, Tina M.
AU - Luers, Aimée J.
AU - Eugenin, Eliseo A.
AU - Javitch, Jonathan A.
AU - Berman, Joan W.
N1 - Funding Information:
These data have significant implications for HIV and drug abuse. We hypothesize that a common mechanism by which drugs of abuse, such as methamphetamine and cocaine, could intensify HIV infection in the brain is through the ability of these drugs to increase extracellular DA levels in the CNS. Our data suggest that increased extracellular DA could induce increased HIV infection of CNS monocytes/macrophages. This hypothesis is supported by the enhancement of HIV replication in MDMs by selective activation of a D2-like DR by the agonist quinpirole and by the presence of active D2R on the surface of MDMs. The D2-like DR-mediated increase in macrophage infection would then lead to higher viral loads and greater production of neurotoxic factors, thereby accelerating and increasing the severity of HIV-mediated neurological damage. The enhanced neuropathology would be particularly pronounced in DA-rich regions of the brain, such as the basal ganglia, providing an explanation for the higher levels of neurological damage seen in these regions during HIV infection. 18,59 The high levels of extracellular DA produced by drug abuse could also potentiate the development of HIV-induced neurological damage by modulating intracellular signaling and contributing to the functional dysregulation of both infected and uninfected macrophages.
PY - 2009/9
Y1 - 2009/9
N2 - The prevalence of human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) that result from HIV infection of the central nervous system is increasing. Macrophages, the primary target for HIV within the central nervous system, play a central role in HIV-induced neuropathogenesis. Drug abuse exacerbates HAND, but the mechanism(s) by which this increased neuropathology results in more severe forms of HAND in HIV-infected drug abusers is unclear. The addictive and reinforcing effects of many drugs of abuse, such as cocaine and methamphetamine, are mediated by increased extracellular dopamine in the brain. We propose a novel mechanism by which drugs of abuse intensify HIV neuropathogenesis through direct effects of the neurotransmitter dopamine on HIV infection of macrophages. We found that macrophages express dopamine receptors 1 and 2, and dopamine activates macrophages by increasing ERK 1 phosphorylation. Our results demonstrate for the first time that dopamine increases HIV replication in human macrophages and that the mechanism by which dopamine mediates this change is by increasing the total number of HIV-infected macrophages. This increase in HIV replication is mediated by activation of dopamine receptor 2. These findings suggest a common mechanism by which drugs of abuse enhance HIV replication in macrophages and indicate that the drug abuse-heightened levels of central nervous system dopamine could increase viral replication, thereby accelerating the development of HAND.
AB - The prevalence of human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) that result from HIV infection of the central nervous system is increasing. Macrophages, the primary target for HIV within the central nervous system, play a central role in HIV-induced neuropathogenesis. Drug abuse exacerbates HAND, but the mechanism(s) by which this increased neuropathology results in more severe forms of HAND in HIV-infected drug abusers is unclear. The addictive and reinforcing effects of many drugs of abuse, such as cocaine and methamphetamine, are mediated by increased extracellular dopamine in the brain. We propose a novel mechanism by which drugs of abuse intensify HIV neuropathogenesis through direct effects of the neurotransmitter dopamine on HIV infection of macrophages. We found that macrophages express dopamine receptors 1 and 2, and dopamine activates macrophages by increasing ERK 1 phosphorylation. Our results demonstrate for the first time that dopamine increases HIV replication in human macrophages and that the mechanism by which dopamine mediates this change is by increasing the total number of HIV-infected macrophages. This increase in HIV replication is mediated by activation of dopamine receptor 2. These findings suggest a common mechanism by which drugs of abuse enhance HIV replication in macrophages and indicate that the drug abuse-heightened levels of central nervous system dopamine could increase viral replication, thereby accelerating the development of HAND.
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U2 - 10.2353/ajpath.2009.081067
DO - 10.2353/ajpath.2009.081067
M3 - Article
C2 - 19661443
AN - SCOPUS:70349237001
VL - 175
SP - 1148
EP - 1159
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 3
ER -