Human Immunodeficiency Virus (HIV) Infection of Human Macrophages Is Increased by Dopamine

Abstract

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.

Drugs of Abuse, Dopamine, and HIV-Associated Neurocognitive Disorders/HIV-Associated Dementia

“…A few investigators have used in vitro studies investigating the role of dopamine in HIV replication using lymphocytes or macrophages [18,41,42]. In an early study, Rohr et al [41] showed that dopamine (100 μM) stimulated HIV-1 transcription and replication (p24 antigen) in Jurkat T cells (T lymphocytes) and in peripheral blood mononuclear cells (PBMC).…”

“…Furthermore, exposure to most drugs of abuse increases brain levels of dopamine well beyond basal levels and levels associated with "natural rewards" (e.g., food, sex) [11][12][13][14][15]. Finally, dopamine has been implicated in HIV and simian immunodeficiency virus (SIV)-induced brain pathology [16,17], and shown to promote HIV replication in macrophages [18]. The purpose of this review is to evaluate the potential role of dopamine in the development of HAND/HAD and in the exacerbation of these conditions by drugs of abuse.…”

Oxidative Stress in Human Health and Disease

“…Over production of NO has been suggested to also increase HIV-1 replication. HIV-1 infection not only causes an increase in ROS generation but also leads to depletion of protective antioxidants in particular, glutathione (138,144). Thus HIV disease is characterized by chronic oxidative stress which drives disease pathogenesis.…”

HIV-Related Neurocognitive Disorders and Drugs of Abuse: Mired in Confound, Surrounded by Risk

“…Commonly abused substances like alcohol, the opioids, other sedatives, the stimulants, marijuana, or more exotic substances like hallucinogens, combinations, or socalled 'designer drugs,' synthetic cannabinoids, etc., have almost all been associated with either cognitive or neuronal dysfunction or laboratory-derived brain damage on mammals. [22][23][24][25][26][27][28][29][30][31].…”