title: Methamphetamine enhances HIV-1 infectivity in monocyte derived dendritic cells.
abstract: The US is currently experiencing an epidemic of methamphetamine (Meth) use as a recreational drug. Recent studies also show a high prevalence of HIV-1 infection among Meth users. We report that Meth enhances HIV-1 infectivity of dendritic cells as measured by multinuclear activation of a galactosidase indicator (MAGI) cell assay, p24 assay, and LTR-RU5 amplification. Meth induces increased HIV-1 infection in association with an increase in the HIV-1 coreceptors, CXCR4 and CCR5, and infection is mediated by downregulation of extracellular-regulated kinase (ERK2) and the upregulation of p38 mitogen-activated protein kinase (MAPK). A p38 inhibitor (SB203580) specifically reversed the Meth-induced upregulation of the CCR5 HIV-1 coreceptor. The dopamine D2 receptor antagonist RS +/- sulpiride significantly reversed the Meth-induced upregulation of CCR5, demonstrating that the Meth-induced effect is mediated via the D2 receptor. These studies report for the first time that Meth fosters HIV-1 infection, potentially via upregulating coreceptor gene expression. Further, Meth mediates its regulatory effects via dopamine receptors and via downregulating ERK2 with a reciprocal upregulation of p38 MAPK. Elucidation of the role of Meth in HIV-1 disease susceptibility and the mechanism through which Meth mediates its effects on HIV-1 infection may help to devise novel therapeutic strategies against HIV-1 infection in high-risk Meth-using HIV-1-infected subjects.
authors.affiliation: Department of Immunology, College of Medicine, Florida International University, Miami, FL 33155, USA. nairm@fiu.edu
authors.forename: Madhavan P N
authors.initials: MP
authors.lastname: Nair
authors.forename: Zainulabedin M
authors.initials: ZM
authors.lastname: Saiyed
authors.forename: Narayanan
authors.initials: N
authors.lastname: Nair
authors.forename: Nimisha H
authors.initials: NH
authors.lastname: Gandhi
authors.forename: Jose W
authors.initials: JW
authors.lastname: Rodriguez
authors.forename: Nawal
authors.initials: N
authors.lastname: Boukli
authors.forename: Elias
authors.initials: E
authors.lastname: Provencio-Vasquez
authors.forename: Robert M
authors.initials: RM
authors.lastname: Malow
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Miguez-Burbano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D015153:Blotting, Western; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000821:virology*; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D051528:Guanylate Kinases; D016655:HIV Core Protein p24 / Q000096:biosynthesis / Q000235:genetics; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D007700:Kinetics; D008694:Methamphetamine / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000821:virology*; D010084:Oxidation-Reduction; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; D018765:Dopamine Uptake Inhibitors; D016655:HIV Core Protein p24; D012367:RNA, Viral; D017448:Receptors, Dopamine D2; D008694:Methamphetamine; D051528:Guanylate Kinases; C113338:MAGI1 protein, human; D004298:Dopamine