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.

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Acknowledgements

This work was supported in part by the National Institute on Drug Abuse Grants RO1-DA012366, RO1-DA014218, RO1-DA015628, RO1-DA021537, and RO1AA017405.

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Correspondence to Madhavan P. N. Nair.

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Nair, M.P.N., Saiyed, Z.M., Nair, N. et al. Methamphetamine Enhances HIV-1 Infectivity in Monocyte Derived Dendritic Cells. J Neuroimmune Pharmacol 4, 129–139 (2009). https://doi.org/10.1007/s11481-008-9128-0

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Keywords

  • dendritic cells
  • HIV-1 infectivity
  • MAGI assay
  • dopamine D2 receptor
  • p38 MAPK
  • chemokine receptors