Methamphetamine enhances HIV-1 infectivity in monocyte derived dendritic cells.
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.
Nair
Madhavan P N
MP
Department of Immunology, College of Medicine, Florida International University, Miami, FL 33155, USA. nairm@fiu.edu
Saiyed
Zainulabedin M
ZM
Nair
Narayanan
N
Gandhi
Nimisha H
NH
Rodriguez
Jose W
JW
Boukli
Nawal
N
Provencio-Vasquez
Elias
E
Malow
Robert M
RM
Miguez-Burbano
Maria Jose
MJ
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
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