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

2014 ◽  
Vol 89 (2) ◽  
pp. 1024-1035 ◽  
Author(s):  
Nazira El-Hage ◽  
Myosotys Rodriguez ◽  
Seth M. Dever ◽  
Ruturaj R. Masvekar ◽  
David A. Gewirtz ◽  
...  
Keyword(s):  
Viral Replication ◽  
Drugs Of Abuse ◽  
Inflammatory Responses ◽  
Interactive Effect ◽  
Opioid Abuse ◽  
Microglial Cells ◽  
Drug Abusers ◽  
Autophagosome Formation ◽  
Increased Risk ◽  
Hiv 1

ABSTRACTMicroglia are the predominant resident central nervous system (CNS) cell type productively infected by HIV-1, and play a key role in the progression of HIV-associated dementia (HAD). Moreover, neural dysfunction and progression to HAD are accelerated in opiate drug abusers. In the present study, we examined the role of the autophagy pathway in the neuropathogenesis of HIV-1 using primary human microglial cells and determined whether opiates converge at this point. Infection of microglia with the HIV-1SF162macrophage-tropic strain resulted in increased Beclin1 expression, accompanied by an increase of LC3 protein levels and accumulation of LC3 reporter RFP+GFP+(yellow) puncta, suggesting that HIV-1 infection triggers autophagosome formation without promoting protein degradation by the lysosome. Conversely, coexposure with HIV-1 and morphine significantly decreased virus-induced Beclin1 expression and autophagosome formation. Exploration of the possible mechanism(s) used by morphine to disrupt the autophagic process unveiled a significant increase in intracellular pH, which coincided with a reduction in the formation of acidic vesicular organelles and in autophagolysosome formation. Small interfering RNA targetingBECN1, a gene critical for autophagosome formation, significantly reduced viral replication and the virus-induced inflammatory responses. Conversely, morphine-enhanced viral replication and inflammatory responses were not affected by gene silencing with siBeclin1, suggesting that the interactive effect of morphine in HIV-1 pathogenesis is mediated through a Beclin1-independent mechanism. These novel findings may have important implications on the connections between autophagy and HIV-1 pathogenesis mediated by microglial cells in opioid-abusing individuals.IMPORTANCEAbout 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.

Perspective food addiction, caloric restriction, and dopaminergic neurotransmission

2013 ◽  
Vol 25 (5) ◽  
pp. 257-267
Author(s):  
Arwen Urrsula Malgorzata Stankowska ◽  
Albert Gjedde
Keyword(s):  
Caloric Restriction ◽  
Sensation Seeking ◽  
Drugs Of Abuse ◽  
Food Addiction ◽  
Eating Behaviour ◽  
Drug Abusers ◽  
Obese People ◽  
Dopaminergic Neurotransmission ◽  
Increased Risk ◽  
Risk Of Relapse

People attempt to change their lifestyle when obesity impairs their quality of life. The attempts often fail when multiple habits must be changed in unison. Here we explore relations among food addiction, the neurobiology of habits, and caloric restriction, when people seek to return to normal eating behaviour, with particular emphasis on the role of dopaminergic neurotransmission.Severely obese individuals have specific neurobiological characteristics in common with drug abusers, including low availability of dopamine receptors in the striatum, impaired neuronal responses to dopamine, and reduced activity in prefrontal regions of the cerebral cortex. The neurobiological characteristics suggest that obese people also have a pathological dependence in common with addicts, in the form of food addiction.Malnutrition and dieting both relate to binge eating, possibly as a compensation for a reduced cognitive reward condition. The combination of caloric restriction and food addiction imparts a high risk of relapse as a result of further reduction of dopaminergic neurotransmission and the subsequent loss of reward. As with drugs of abuse, ingestion of large quantities of sugar in circumstances of uncontrolled eating increases dopamine release in the nucleus accumbens. This and other evidence suggests that abuse of food is a habit learned by means of mechanisms centred in the basal ganglia, with an increased risk of relapse in the presence of associative amplifiers. This risk is predicted by the relationship between dopamine receptor availability in the striatum and sensation-seeking in the form of an inverted U, suggested by recent findings, consistent with two opposite states of hypodopaminergic and hyperdopaminergic neuromodulation.

Abstract 100: HIV Protein Tat Induces Macrophage Dysfunction and Atherosclerosis Development in LDLR-deficient Mice

2020 ◽  
Vol 40 (Suppl_1) ◽  
Author(s):  
Zhaojie Meng ◽  
Weiwei Lu ◽  
Taesik Gwag ◽  
Changcheng Zhou
Keyword(s):  
Inflammatory Responses ◽  
Atherosclerotic Lesion ◽  
Iκb Kinase ◽  
Increased Risk ◽  
Macrophage Dysfunction ◽  
Atherosclerosis Development ◽  
And Migration ◽  
The Impact ◽  
Hiv 1

Introduction: As the average lifespan of HIV-infected patients receiving anti-retroviral therapy lengthens, morbidity and mortality from cardiovascular disease pose considerable challenges. HIV infection is consistently associated with increased risk of atherosclerosis development, but the underlying mechanisms remain elusive. HIV-1 Tat protein, a transcriptional activator of HIV virus, has been shown to activate NF-κB signaling and promote inflammation in vitro. However, the atherogenic effects of HIV-1 Tat have not been investigated in vivo. Macrophage is one of the major cell types involved in the initiation and progression of atherosclerosis. We and others have previously demonstrated that NF-κB signaling functions in macrophages to regulate atherogenesis. This study aims to investigate the impact of HIV-1 Tat exposure on macrophage functions and atherogenesis. Hypothesis: HIV-1 Tat activates IκB kinase β (IKKβ), a central coordinator in inflammation through activation of NF-κB, to induce macrophage dysfunction and atherosclerosis development. Methods: To investigate the effects of HIV-1 Tat on macrophage IKKβ signaling and atherosclerosis development in vivo, myeloid-specific IKKβ-deficient LDLR-deficient (IKKβ ΔMye LDLR -/- ) mice and their control littermates (IKKβ F/F LDLR -/- ) were exposed to recombinant HIV-1 Tat for 12 weeks. The effects of HIV-1 Tat on macrophage functions including inflammatory responses, adhesion and migration properties were also studied. Results and Conclusions: HIV-1 Tat significantly increased atherosclerotic lesion size in aortic root and brachiocephalic artery of IKKβ F/F LDLR -/- but not IKKβ ΔMye LDLR -/- mice. Deficiency of myeloid IKKβ attenuated macrophage inflammatory responses and decreased atherosclerotic lesional inflammation in IKKβ ΔMye LDLR -/- mice. In addition, HIV-1 Tat stimulated adhesion and migration properties of control macrophages but had no effects on IKKβ-deficient macrophages. In conclusion, our findings reveal the atherogenic effects of HIV-1 Tat in vivo and demonstrate a pivot role of myeloid IKKβ in HIV-1 Tat-driven atherogenesis.

scholarly journals The Nuclear Receptor Chicken Ovalbumin Upstream Promoter Transcription Factor Interacts with HIV-1 Tat and Stimulates Viral Replication in Human Microglial Cells

2000 ◽  
Vol 275 (4) ◽  
pp. 2654-2660 ◽  
Author(s):  
Olivier Rohr ◽  
Christian Schwartz ◽  
Christiane Hery ◽  
Dominique Aunis ◽  
Marc Tardieu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Viral Replication ◽  
Nuclear Receptor ◽  
Microglial Cells ◽  
Upstream Promoter ◽  
Hiv 1 ◽  
Chicken Ovalbumin

scholarly journals Induction of HIF-1α by HIV-1 Infection in CD4+T Cells Promotes Viral Replication and Drives Extracellular Vesicle-Mediated Inflammation

mBio ◽  
2018 ◽  
Vol 9 (5) ◽  
Author(s):  
Gabriel Duette ◽  
Pehuen Pereyra Gerber ◽  
Julia Rubione ◽  
Paula S. Perez ◽  
Alan L. Landay ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Viral Replication ◽  
Extracellular Vesicles ◽  
Immune Activation ◽  
Antiretroviral Treatment ◽  
Inflammatory Responses ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1Α ◽  
Hiv 1

ABSTRACTChronic immune activation and inflammation are hallmarks of HIV-1 infection and a major cause of serious non-AIDS events in HIV-1-infected individuals on antiretroviral treatment (ART). Herein, we show that cytosolic double-stranded DNA (dsDNA) generated in infected CD4+T cells during the HIV-1 replication cycle promotes the mitochondrial reactive oxygen species (ROS)-dependent stabilization of the transcription factor hypoxia-inducible factor 1α (HIF-1α), which in turn, enhances viral replication. Furthermore, we show that induction of HIF-1α promotes the release of extracellular vesicles (EVs). These EVs foster inflammation by inducing the secretion of gamma interferon by bystander CD4+T cells and secretion of interleukin 6 (IL-6) and IL-1β by bystander macrophages through an HIF-1α-dependent pathway. Remarkably, EVs obtained from plasma samples from HIV-1-infected individuals also induced HIF-1α activity and inflammation. Overall, this study demonstrates that HIF-1α plays a crucial role in HIV-1 pathogenesis by promoting viral replication and the release of EVs that orchestrate lymphocyte- and macrophage-mediated inflammatory responses.IMPORTANCEHuman immunodeficiency virus type 1 (HIV-1) is a very important global pathogen that preferentially targets CD4+T cells and causes acquired immunodeficiency syndrome (AIDS) if left untreated. Although antiretroviral treatment efficiently suppresses viremia, markers of immune activation and inflammation remain higher in HIV-1-infected patients than in uninfected individuals. The hypoxia-inducible factor 1α (HIF-1α) is a transcription factor that plays a fundamental role in coordinating cellular metabolism and function. Here we show that HIV-1 infection induces HIF-1α activity and that this transcription factor upholds HIV-1 replication. Moreover, we demonstrate that HIF-1α plays a key role in HIV-1-associated inflammation by promoting the release of extracellular vesicles which, in turn, trigger the secretion of inflammatory mediators by noninfected bystander lymphocytes and macrophages. In summary, we identify that the coordinated actions of HIF-1α and extracellular vesicles promote viral replication and inflammation, thus contributing to HIV-1 pathogenesis.

HIV-1 Associated Topoisomerase IIβ Kinase: A Potential Pharmacological Target for Viral Replication

2013 ◽  
Vol 19 (26) ◽  
pp. 4776-4786 ◽  
Author(s):  
Kannapiran Ponraj ◽  
Maddela Prabhakar ◽  
R.S. Rathore ◽  
Akhila Bommakanti ◽  
Anand Kondapi
Keyword(s):  
Viral Replication ◽  
Topoisomerase Ii ◽  
Pharmacological Target ◽  
Hiv 1 ◽  
Kinase A

scholarly journals Antigen-driven CD4+ T cell and HIV-1 dynamics: Residual viral replication under highly active antiretroviral therapy

1999 ◽  
Vol 96 (26) ◽  
pp. 15167-15172 ◽  
Author(s):  
N. M. Ferguson ◽  
F. deWolf ◽  
A. C. Ghani ◽  
C. Fraser ◽  
C. A. Donnelly ◽  
...  
Keyword(s):  
T Cell ◽  
Antiretroviral Therapy ◽  
Viral Replication ◽  
Highly Active Antiretroviral Therapy ◽  
Cd4 T Cell ◽  
Highly Active ◽  
Hiv 1

scholarly journals Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In Vitro

2021 ◽  
Vol 22 (6) ◽  
pp. 3163
Author(s):  
Hirofumi Ohashi ◽  
Feng Wang ◽  
Frank Stappenbeck ◽  
Kana Tsuchimoto ◽  
Chisa Kobayashi ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Viral Replication ◽  
Cultured Cells ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Membrane Vesicles ◽  
Drug Candidates ◽  
Increased Risk ◽  
Derivatives Of

The development of effective antiviral drugs targeting the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is urgently needed to combat the coronavirus disease 2019 (COVID-19). We have previously studied the use of semi-synthetic derivatives of oxysterols, oxidized derivatives of cholesterol as drug candidates for the inhibition of cancer, fibrosis, and bone regeneration. In this study, we screened a panel of naturally occurring and semi-synthetic oxysterols for anti-SARS-CoV-2 activity using a cell culture infection assay. We show that the natural oxysterols, 7-ketocholesterol, 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, and 27-hydroxycholesterol, substantially inhibited SARS-CoV-2 propagation in cultured cells. Among semi-synthetic oxysterols, Oxy210 and Oxy232 displayed more robust anti-SARS-CoV-2 activities, reducing viral replication more than 90% at 10 μM and 99% at 15 μM, respectively. When orally administered in mice, peak plasma concentrations of Oxy210 fell into a therapeutically relevant range (19 μM), based on the dose-dependent curve for antiviral activity in our cell-based assay. Mechanistic studies suggest that Oxy210 reduced replication of SARS-CoV-2 by disrupting the formation of double-membrane vesicles (DMVs); intracellular membrane compartments associated with viral replication. Our study warrants further evaluation of Oxy210 and Oxy232 as a safe and reliable oral medication, which could help protect vulnerable populations with increased risk of developing COVID-19.

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