Methamphetamine enhances HIV-1 infectivity in monocyte derived dendritic cells

J Neuroimmune Pharmacol. 2009 Mar;4(1):129-39. doi: 10.1007/s11481-008-9128-0. Epub 2008 Oct 29.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Blotting, Western
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Cells, Cultured
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Dendritic Cells / drug effects*
  • Dendritic Cells / virology*
  • Dopamine / metabolism
  • Dopamine Uptake Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Flow Cytometry
  • HIV Core Protein p24 / biosynthesis
  • HIV Core Protein p24 / genetics
  • HIV-1 / pathogenicity*
  • Humans
  • Kinetics
  • Methamphetamine / pharmacology*
  • Monocytes / drug effects*
  • Monocytes / virology*
  • Oxidation-Reduction
  • RNA, Viral / biosynthesis
  • RNA, Viral / genetics
  • Receptors, Dopamine D2 / drug effects
  • Receptors, Dopamine D2 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Cell Adhesion Molecules, Neuronal
  • Dopamine Uptake Inhibitors
  • HIV Core Protein p24
  • RNA, Viral
  • Receptors, Dopamine D2
  • Methamphetamine
  • MAGI1 protein, human
  • Dopamine