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 dose-dependent 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.
Highlights
Human Immunodeficiency Virus type 1 (HIV) enters the central nervous system (CNS) within 8 days of initial infection [1] and leads to the development of HIV-associated neurological disorders (HAND) in 40–70% of individuals [2,3,4,5,6]
Replication in macrophages were due to an increase in viral entry, primary human monocyte-derived macrophages (MDM) were infected with different concentrations of HIVBaL virions harboring an active b-lactamase enzyme (b-lac HIV)
Infection with b-lac HIV using a multiplicity of infection (MOI) of 0.002 for 4 hours resulted in infection of 1.0% to 11.9% of MDM, 1.3% to 27.4% using an MOI of 0.005 and 1.4% to 37.8% of cells using an MOI of 0.01 (Figure 1A, MOI 0.002, n = 11; 1B, MOI 0.005, n = 6; 1C, MOI 0.01, n = 16)
Summary
Human Immunodeficiency Virus type 1 (HIV) enters the central nervous system (CNS) within 8 days of initial infection [1] and leads to the development of HIV-associated neurological disorders (HAND) in 40–70% of individuals [2,3,4,5,6]. Macrophages are critical to HIV mediated neuropathogenesis [13,14,15,16] and may serve as viral reservoirs within the CNS [17,18]. Macrophages release inflammatory mediators and neurotoxic viral and host proteins, contributing to chronic neuroinflammation and neurotoxicity [16,19,20]. Infection of CNS macrophages is central to HIV-associated neuroinflammation and neurocognitive dysfunction. Studies in SIV-infected rhesus macaques show that increases in extracellular dopamine correlate with increased CNS viral loads [25,26]. The effects of dopamine on macrophage function, and the signaling pathways by which these effects are mediated, have not been studied extensively
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