Methamphetamine potentiates HIV-1 gp120-mediated autophagy via Beclin-1 and Atg5/7 as a pro-survival response in astrocytes

Abstract

Methamphetamine (METH), a commonly used controlled substance, is known to exacerbate neuropathological dysfunction in HIV-infected individuals. The neuropathological manifestation results from cell death or dysfunction in the central nervous system (CNS) wherein autophagy is expected to have an important role. Autophagy is generally considered protective during deprivation/stress. However, excessive autophagy can be destructive, leading to autophagic cell death. This study was designed to investigate if METH and HIV-1 gp120 interact to induce autophagy in SVGA astrocytes, and whether autophagy is epiphenomenal or it has a role in METH- and gp120-induced cytotoxicity. We found that METH and gp120 IIIb caused an increase in LC3II level in astrocytes in a dose- and time-dependent manner, and the level of LC3II was further increased when the cells were treated with METH and gp120 IIIb in combination. Next, we sought to explore the mechanism by which METH and gp120 induce the autophagic response. We found that METH induces autophagy via opioid and metabotropic glutamate receptor type 5 (mGluR5) receptors. Other than that, signaling proteins Akt, mammalian target of rapamycin (mTOR), Beclin-1, Atg5 and Atg7 were involved in METH and gp120-mediated autophagy. In addition, long-term treatment of METH and gp120 IIIb resulted in cell death, which was exacerbated by inhibition of autophagy. This suggests that autophagy functions as a protective response against apoptosis caused by METH and gp120. This study is novel and clinically relevant because METH abuse among HIV-infected populations is highly prevalent and is known to cause exacerbated neuroAIDS.

Importance of Autophagy in Mediating Human Immunodeficiency Virus (HIV) and Morphine-Induced Metabolic Dysfunction and Inflammation in Human Astrocytes

“…While assessing the role of autophagy in oxidative stress, we measured RNS production and saw that increasing autophagy by rapamycin treatment reversed HIV-induced NO release by astrocytes ( Figure 2 F). Concurring with other studies, a decreased rate in autophagy aggravated the toxic insult of the virus [ 44 ]. We were able to detect a similar trend, albeit not significant in the modulation of HIV-induced ROS release by the autophagy pathway ( Figure 2 A–C).…”

“…More pertinent to our study, studies have shown a protective role of autophagy on astrocytes upon injury or HIV infection [ 43 ]. Also, a more recent report showed that the HIV protein gp120 in combination with methamphetamine induced autophagy in astrocytes [ 44 ]. It is therefore clear that the role of autophagy in HIV-induced astrocyte dysfunction, specifically in the context of opioid abuse, has not been extensively explored.…”

Interplay between Autophagy, Exosomes and HIV-1 Associated Neurological Disorders: New Insights for Diagnosis and Therapeutic Applications

“…Moreover, the HIV-1 protein Nef, which is expressed abundantly in infected human astrocytes, blocks autophagic degradation that may lead to neuropathogenesis [ 87 ]. A more recent report showed that the HIV-1 protein gp120 in combination with methamphetamine additively induced autophagy in astrocytes, and inhibition of autophagy resulted in acceleration of cell death induced by methamphetamine and gp120 [ 110 ]. This suggests that autophagy functions as a protective response against apoptosis caused by methamphetamine and gp120.…”

Role of Autophagy in HIV Pathogenesis and Drug Abuse

“…We have also concluded from this study that the autophagy was mediated by signaling pathway involving mTOR, Beclin-1, Atg5, and Atg7. We further showed that autophagy inhibitors exacerbated gp120/methamphetamine-mediated cell death suggesting a protective role of autophagy in astrocyte death [146]. In spite of the fact that only limited knowledge is available regarding cumulative effect of DOA and HIV-1, it is logical to believe that autophagy plays an important role in HIV-1 pathogenesis.…”