Abstract
Drug abuse is a major comorbidity of HIV infection and cognitive disorders are often more severe in the drug abusing HIV infected population. CD14+CD16+ monocytes, a mature subpopulation of peripheral blood monocytes, are key mediators of HIV neuropathogenesis. Infected CD14+CD16+ monocyte transmigration across the blood brain barrier mediates HIV entry into the brain and establishes a viral reservoir within the CNS. Despite successful antiretroviral therapy, continued influx of CD14+CD16+ monocytes, both infected and uninfected, contributes to chronic neuroinflammation and the development of HIV associated neurocognitive disorders (HAND). Drug abuse increases extracellular dopamine in the CNS. Once in the brain, CD14+CD16+ monocytes can be exposed to extracellular dopamine due to drug abuse. The direct effects of dopamine on CD14+CD16+ monocytes and their contribution to HIV neuropathogenesis are not known. In this study, we showed that CD14+CD16+ monocytes express mRNA for all five dopamine receptors by qRT-PCR and D1R, D5R and D4R surface protein by flow cytometry. Dopamine and the D1-like dopamine receptor agonist, SKF38393, increased CD14+CD16+ monocyte migration that was characterized as chemokinesis. To determine whether dopamine affected cell motility and adhesion, live cell imaging was used to monitor the accumulation of CD14+CD16+ monocytes on the surface of a tissue culture dish. Dopamine increased the number and the rate at which CD14+CD16+ monocytes in suspension settled to the dish surface. In a spreading assay, dopamine increased the area of CD14+CD16+ monocytes during the early stages of cell adhesion. In addition, adhesion assays showed that the overall total number of adherent CD14+CD16+ monocytes increased in the presence of dopamine. These data suggest that elevated extracellular dopamine in the CNS of HIV infected drug abusers contributes to HIV neuropathogenesis by increasing the accumulation of CD14+CD16+ monocytes in dopamine rich brain regions.
Highlights
HIV enters the brain within two weeks of peripheral infection [1,2]
The chronic, low level neuroinflammation that develops as a result of HIV infection of the central nervous system (CNS) is believed to lead to HIV associated neurocognitive disorders (HAND) in 40–70% of infected people, despite the success of combined antiretroviral therapy in reducing viral load in plasma and cerebrospinal fluid [3,4,5]
We demonstrated that dopamine increases the rate and number of CD14+CD16+ monocytes in suspension that settled to the surface of a tissue culture dish
Summary
HIV enters the brain within two weeks of peripheral infection [1,2]. The chronic, low level neuroinflammation that develops as a result of HIV infection of the central nervous system (CNS) is believed to lead to HIV associated neurocognitive disorders (HAND) in 40–70% of infected people, despite the success of combined antiretroviral therapy (cART) in reducing viral load in plasma and cerebrospinal fluid [3,4,5]. HIV infected individuals have increased CNS CXCL12 and CCL2 as a result of infection and activation of resident cells [8,9]. These chemokines can recruit infected and uninfected monocytes into the brain, further contributing to chronic neuroinflammation [8,10,11,12,13,14]. The mature CD14+CD16+ monocyte population preferentially transmigrates across an in vitro human blood brain barrier model in response to CCL2 and is highly permissive to HIV infection [22,23,24]. Uninfected and HIV infected CD14+CD16+ monocyte influx into the CNS contributes to neuroinflammation, CNS infection and establishment of viral reservoirs, and the development of HAND
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