Autophagy Induction by HIV-Tat and Methamphetamine in Primary Midbrain Neuronal Cells of Tree Shrews via the mTOR Signaling and ATG5/ATG7 Pathway.

Jiejie Dai,Dexuan Kuang,Juan Li,Yuanyuan Han,Xiaofeng Zeng,Xiaomei Sun,Pinfen Tong,Zhen Li,Wenguang Wang,Genmeng Yang,Caixia Lu,Chi-Kwan Leung,Na Li

doi:10.3389/fnins.2018.00921

Abstract

Background: Addictive stimulant drugs, such as methamphetamine (METH), increase the risk of exposure to the human immunodeficiency virus-1 (HIV-1) infection and thus predispose individuals to the development of HIV-associated neurocognitive disorders (HANDs). Previous studies have indicated that HIV-Tat (the transactivator of transcription) and METH can synergistically induce autophagy in SH-SY5Y neuroblastoma cells and that autophagy plays a pivotal role in the neuronal dysfunction in HANDs. However, the underlying mechanism of METH-and HIV-Tat-induced neuronal autophagy remains unclear.Methods: We cultured primary midbrain neuronal cells of tree shrews and treated them with METH and HIV-Tat to study the role of METH and HIV-Tat in inducing autophagy. We evaluated the effects of the single or combined treatment of METH and HIV-Tat on the protein expressions of the autophagy-related genes, including Beclin-1 and LC3B, ATG5, and ATG7 in METH and HIV-Tat-induced autophagy. In addition, the presence of autophagosomes in the METH and/or HIV-Tat treatment was revealed using transmission electron microscopy.Results: The results indicated that METH increased the protein levels of LC3B and Beclin-1, and these effects were significantly enhanced by HIV-Tat. Moreover, the results suggested that ATG5 and ATG7 were involved in the METH and HIV-Tat-induced autophagy. In addition, it was found that mTOR inhibition via pharmacological intervention could trigger autophagy and promote METH and HIV-Tat-induced autophagy.Discussion: Overall, this study contributes to the knowledge of the molecular underpinnings of METH and HIV-Tat-induced autophagy in primary midbrain neuronal cells. Our findings may facilitate the development of therapeutic strategies for METH-and HIV-Tat-induced autophagy in HANDs.

Highlights

The clinical implementation of antiretroviral therapy has significantly prolonged the lifetime of the human immunodeficiency virus (HIV-1)-infected population, HIVassociated neurocognitive disorders (HANDs) remain a critical concern in a significant number of human immunodeficiency virus-1 (HIV-1) positive individuals (Rumbaugh et al, 2008; Maubert et al, 2015)
When the primary neuronal cells of tree shrews were cultured for 7 days, the cells were identified as neurons (Figure 1A); we determined the expression levels of autophagy-related protein markers (Beclin-1 and LC3B) in the METH-treated primary neuronal cells
It has been shown that HIV-Tat and METH have synergistic effects on inducing autophagy in SH-SY5Y human neuroblastoma cells, which act as dopaminergic neuronal cells (Qi et al, 2011; Zeng et al, 2018), the mechanism that underlies the induction of autophagy via HIV-Tat and METH has not been elucidated

Summary

Introduction

The clinical implementation of antiretroviral therapy has significantly prolonged the lifetime of the human immunodeficiency virus (HIV-1)-infected population, HIVassociated neurocognitive disorders (HANDs) remain a critical concern in a significant number of HIV-1 positive individuals (Rumbaugh et al, 2008; Maubert et al, 2015). The common use of recreational drugs increases the incidence and severity of HANDs and other HIV-1-associated pathological disorders within HIV-1-infected individuals (Sharma et al, 2011; Hauser et al, 2012; Nair and Samikkannu, 2012). Addictive stimulant drugs, such as methamphetamine (METH), increase the risk of exposure to the human immunodeficiency virus-1 (HIV-1) infection and predispose individuals to the development of HIV-associated neurocognitive disorders (HANDs). The underlying mechanism of METH-and HIV-Tat-induced neuronal autophagy remains unclear

Methods

Results

Discussion

Conclusion