HIV-1 and Morphine Regulation of Autophagy in Microglia: Limited Interactions in the Context of HIV-1 Infection and Opioid Abuse

Abstract

About 50% of individuals infected with HIV-1 will develop some sort of neurocognitive impairment that cannot be prevented nor eradicated by antiretroviral therapy. The neuropathogenesis is mostly due to inflammatory responses by infected microglia, the resident immune cells of the brain. Cognitive disorders may also be associated with drugs of abuse. In fact, opioid drug users have an increased risk of developing neurocognitive disorders with increased progression to dementia. Although the mechanism(s) by which opioids exacerbate the neuropathogenesis of HIV-1 are not entirely known, it is well accepted that glia are critical to opiate responses. This study gives us new insight into possible autophagic mechanism(s) in microglia that control HIV-1 replication and virus-induced inflammation in the context of opioid abuse and should greatly improve our knowledge in the pathogenesis of HIV-1 resulting from substance abuse to provide a better understanding for the design of candidate antiviral therapies targeting drug-abusing individuals.

Cocaine induces astrocytosis through ER stress-mediated activation of autophagy

“…[40][41][42][43] In addition to the known etiological agents, drugs of abuse such as cocaine, morphine and amphetamines, are also known to induce ER stress and autophagy in various cell types of the CNS, thereby exacerbating the disease pathology. 14,34,44 Several reports have implicated a central role for ER stress in the induction of autophagy in the pathogenesis of various neurodegenerative diseases mediated by diverse stressors. [45][46][47][48][49][50] In the current study, we demonstrate for the first time a molecular link between ER stress-mediated activation of autophagy and the induction of astrogliosis that is accompanied with the release of proinflammatory cytokines in cocainetreated human astrocytes.…”

“…28 The cellular and molecular mechanism(s) leading to astrogliosis mediated by diverse agents as well as the related neuroinflammatory pathways that trigger astrogliosis are still areas of active investigation. While the role of drugs of abuse, such as morphine and methamphetamine, on induction of apoptosis, HIV disease progression, neuronal injury and neurodegeneration has been well established, [34][35][36][37][38][39] information in how the drugs influences astrogliosis and the role of autophagy in this process is very limited.…”

Enhanced autophagy in pulmonary endothelial cells on exposure to HIV-Tat and morphine: Role in HIV-related pulmonary arterial hypertension

“…Contrary to this, El-Hage et al previously have demonstrated decrease in autophagy on combined morphine-Tat treatment in human microglia. 51 Although Dever et al 52 also report lower autophagy activity in neurons on MCT coexposure initially at 8 h post-treatment, increased autophagy was observed at 24 h of combined treatment, again establishing cell-type-dependent differences in the autophagy response.…”

Cocaine-Mediated Autophagy in Astrocytes Involves Sigma 1 Receptor, PI3K, mTOR, Atg5/7, Beclin-1 and Induces Type II Programed Cell Death

“…However, role of autophagy in cocaine-mediated deleterious effect in the brain remains poorly understood. Several recent studies with other psychostimulants suggest involvement of autophagy in neurotoxicity [30,33]. For example, morphine-mediated autophagy is responsible for the development of morphine antinociceptive tolerance [39] and methamphetamine has been reported to induce cell death via autophagy [40].…”