Methamphetamine Enhances HIV-1 Infectivity in Monocyte Derived Dendritic Cells

• Published in: Journal of neuroimmune pharmacology 2009-03, Vol.4 (1), p.129-139
• Main Authors: Nair, Madhavan P. N., Saiyed, Zainulabedin M., Nair, Narayanan, Gandhi, Nimisha H., Rodriguez, Jose W., Boukli, Nawal, Provencio-Vasquez, Elias, Malow, Robert M., Miguez-Burbano, Maria Jose
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Biomedical and Life Sciences; Biomedicine; Blotting, Western; Cell Adhesion Molecules; Cell Adhesion Molecules, Neuronal - metabolism; Cell Biology; Cells, Cultured; Cytosol - drug effects; Cytosol - metabolism; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - virology; Dopamine; Dopamine - metabolism; Dopamine Uptake Inhibitors - pharmacology; Dose-Response Relationship, Drug; Flow Cytometry; Gene expression; Guanylate Kinases; HIV Core Protein p24 - biosynthesis; HIV Core Protein p24 - genetics; HIV-1 - pathogenicity; Human immunodeficiency virus 1; Humans; Immunology; Infections; Kinases; Kinetics; Methamphetamine; Methamphetamine - pharmacology; Monocytes - drug effects; Monocytes - virology; Neurosciences; Original Article; Oxidation-Reduction; Pharmacology/Toxicology; Receptors, Dopamine D2 - drug effects; Receptors, Dopamine D2 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral - biosynthesis; RNA, Viral - genetics; Virology
• ISSN: 1557-1890; 1557-1904
• DOI: 10.1007/s11481-008-9128-0

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.