Human immunodeficiency virus (HIV) infection of human macrophages is increased by dopamine: a bridge between HIV-associated neurologic disorders and drug abuse.
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.
Gaskill
Peter J
PJ
Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Calderon
Tina M
TM
Luers
Aimée J
AJ
Eugenin
Eliseo A
EA
Javitch
Jonathan A
JA
Berman
Joan W
JW
D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology*; D015259:Dopamine Agents / Q000378:metabolism / Q000494:pharmacology; D006678:HIV / Q000187:drug effects / Q000502:physiology*; D015658:HIV Infections / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D006801:Humans; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism / Q000821:virology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction; D019966:Substance-Related Disorders / Q000150:complications / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
D015259:Dopamine Agents; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D048052:Mitogen-Activated Protein Kinase 3; D004298:Dopamine