title: Dopamine receptor activation increases HIV entry into primary human macrophages.
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.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gaskill
authors.affiliation: Department of Psychiatry and Pharmacology, Columbia University, New York, New York, United States of America.
authors.forename: Hideaki H
authors.initials: HH
authors.lastname: Yano
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Ganjam V
authors.initials: GV
authors.lastname: Kalpana
authors.affiliation: Department of Psychiatry and Pharmacology, Columbia University, New York, New York, United States of America.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Javitch
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America; Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Joan W
authors.initials: JW
authors.lastname: Berman
mesh_terms: D000577:Amides / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005475:Flupenthixol / Q000494:pharmacology; D015870:Gene Expression; D023581:HIV Fusion Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D061251:Primary Cell Culture; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000577:Amides; D065100:CCR5 Receptor Antagonists; C584933:CCR5 protein, human; D018492:Dopamine Antagonists; D023581:HIV Fusion Inhibitors; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C119369:TAK 779; D005475:Flupenthixol; D004298:Dopamine