Methamphetamine functions as a novel CD4+ T-cell activator via the sigma-1 receptor to enhance HIV-1 infection

Anil Prasad,Shuxian Jiang,Kaycie Lawson,Rutuja Kulkarni,Jerome E Groopman,Ashutosh Shrivastava

doi:10.1038/s41598-018-35757-x

Abstract

Methamphetamine (Meth) exacerbates HIV-1 pathobiology by increasing virus transmission and replication and accelerating clinical progression to AIDS. Meth has been shown to alter the expression of HIV-1 co-receptors and impair intrinsic resistance mechanisms of immune cells. However, the exact molecular mechanisms involved in augmenting HIV-1 replication in T-cells are still not yet clear. Here, we demonstrate that pretreatment with Meth of CD4+ T-cells enhanced HIV-1 replication. We observed upregulation of CD4+ T-cell activation markers and enhanced expression of miR-34c-5p and miR-155 in these cells. Further, we noted activation of the sigma-1 receptor and enhanced intracellular Ca2+ concentration and cAMP release in CD4+ T-cells upon Meth treatment, which resulted in increased phosphorylation and nuclear translocation of transcription factors NFκB, CREB, and NFAT1. Increased gene expression of IL-4 and IL-10 was also observed in Meth treated CD4+ T-cells. Moreover, proteasomal degradation of Ago1 occurred upon Meth treatment, further substantiating the drug as an activator of T-cells. Taken together, these findings show a previously unreported mechanism whereby Meth functions as a novel T-cell activator via the sigma-1 signaling pathway, enhancing replication of HIV-1 with expression of miR-34c-5p, and transcriptional activation of NFκB, CREB and NFAT1.

Highlights

Meth functions as a novel T-cell activator via the sigma-1 signaling pathway, enhancing replication of HIV-1 with expression of miR-34c-5p, and transcriptional activation of NFκB, cyclic-AMP response element-binding protein (CREB) and NFAT1
Previous studies in in vitro models have demonstrated that Meth enhances HIV-1 replication in T-cells, dendritic cells (DCs), macrophages and neural progenitor cells[11,12,13,14]
The significance of these results is supported by an epidemiological study, which demonstrated increased viral loads in Meth using HIV-1 infected individuals compared with non-users who were infected[28]

Summary

Introduction

Meth functions as a novel T-cell activator via the sigma-1 signaling pathway, enhancing replication of HIV-1 with expression of miR-34c-5p, and transcriptional activation of NFκB, CREB and NFAT1. Studies in animal models have shown that Meth treatment can increase viral load in HIV-1 infected animals[10,11]. Meth can activate G-protein coupled receptors such as trace amine associated receptor 1 (TAAR1), and increase intracellular cyclic adenosine monophosphate (cAMP) levels[20]. Activation of these signaling pathways has been implicated in Meth mediated neuroinflammation[21]. Meth has been shown to modulate intracellular restriction factors by regulating miRNA expression, thereby enhancing HIV-1 infection[22]. A significant downregulation of Ago[2] was observed in the nucleus accumbens of Meth sensitized mice and expression of precursor miRNA was unaltered in these tissues, indicating that Meth may inhibit the Ago protein mediated splicing of precursor miRNA and its maturation[23]

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