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.Human immunodeficiency virus (HIV) enters the central nervous system (CNS) soon after initial infection,¹ resulting in ongoing inflammation and neurological damage that leads to the development of HIV-associated neurocognitive disorders (HAND) in as many as 50% of infected individuals.^2,3 The prevalence of these complications is increasing despite the advent of antiretroviral therapy, due to the longer lifespan of infected individuals on antiretroviral therapies⁴ and the poor ability of most antiretroviral drugs to penetrate the blood-brain barrier.^5,6 HIV is thought to enter the brain through the transmigration of infected monocytes across the blood-brain barrier.^7,8,9,10 Within the CNS, macrophages are the primary source of HIV and the virus spreads primarily through infection of brain macrophages and microglia.^11,12 Infected macrophages produce numerous factors that are neurotoxic and contribute to the neurological damage that occurs in HIV-infected individuals.^13,14,15 Thus, HIV infection and replication within CNS macrophages plays a central role in the development of HANDs.The incidence and severity of HAND are exacerbated by drugs of abuse, such as the psychostimulants cocaine and methamphetamine,^16,17,18,19 which have been shown to increase both HIV neuropathogenesis and viral replication.^{20,21,22,23,24} However, the mechanism(s) by which drugs of abuse enhance HIV-related neuropathologies are not well understood. Dopamine (DA), a neurotransmitter involved in the control of locomotion, cognition, positive reinforcement, and neuroendocrine secretion,²⁵ is central to the action of drugs of abuse. Psychostimulants such as cocaine and methamphetamine exert addictive and reinforcing effects through elevation of extracellular DA levels in the CNS.^{26,27,28,29,30} The use of both cocaine and methamphetamine generates extracellular CNS dopamine levels far higher than those found in the brains of non-drug-abusers.^{26,31,32,33,34,35,36}Dopamine acts through dopamine receptors, which are members of the G-protein coupled seven transmembrane domain family of receptors. Dopamine receptors (DRs) are divided into two subtypes designated D1-like DRs, comprised of dopamine receptor 1 (D1R) and D5R, and D2-like DRs, comprised of D2R, D3R, and D4R.²⁵ Classically, DRs have been studied on neurons, but DR expression has also been reported in several types of peripheral blood leukocytes, including T lymphocytes and monocytes.^37,38,39 Dopamine receptors have been shown to modulate the immune function of T lymphocytes.^25,40,41 A recent study showed D1R on human macrophages,²⁴ but the expression of other DRs and the functions of DRs in this cell type have not been well characterized.In studies with simian immunodeficiency virus-infected macaques, injection with or oral administration of L-DOPA, a DA precursor that crosses the blood-brain barrier, or selegiline, a blocker of DA breakdown by monoamine oxidase, resulted in increased levels of simian immunodeficiency virus in the CNS.^42,43 In addition, infected macaques exhibited an increased incidence of simian immunodeficiency virus encephalitis and induction of a spongiform polioencephalopathy in dopaminergic regions of the CNS.^42,43 These studies suggest that the enhanced extracellular DA elicited by use of drugs like cocaine and methamphetamine could be sufficient to increase HIV replication in the CNS and exacerbate HIV neuropathogenesis. Macrophages play a central role in the development of HIV-induced neuropathology. Thus, examination of DA modulation of HIV infection of macrophages, as well as the characterization of intracellular signaling pathways that are involved in the DA-mediated increase in HIV infectivity, are important to the identification of mechanisms by which drugs of abuse enhance the development of HAND.This report demonstrates that primary human monocyte-derived macrophages (MDMs) inoculated with HIV in the presence of DA exhibit increased levels of viral replication when compared with MDMs inoculated with HIV in the absence of DA. The DA-induced increase in viral replication correlated with an increase in the percentage of MDMs infected with HIV. HIV infection in the presence of the D2R agonist, quinpirole, increased viral replication similarly to DA, while infection in the presence of the D1R agonist, SKF 82958, did not alter HIV replication, suggesting that D2R is involved in the DA-mediated increase in HIV replication. The data also confirm that uninfected MDMs expressed both D1R and D2R on the cell surface and show that endogenous macrophage D2R was active by demonstrating that DA induced extracellular signal regulated kinase 1 (ERK 1) phosphorylation in macrophages through D2R. These results suggest that dopamine-induced increases in HIV replication in macrophages may be an important mechanism by which specific drugs of abuse, characterized by their ability to increase extracellular DA levels in the CNS, exacerbate the neuropathogenesis of HIV infection.