The impact of substance abuse on HIV-mediated neuropathogenesis in the current ART era

Chilunda, Vanessa; Calderon, Tina M.; Martínez-Aguado, Pablo; Berman, Joan W.

doi:10.1016/j.brainres.2019.146426

Cited by 50 publications

(43 citation statements)

References 310 publications

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“…HIV-1 Tat also contains a cysteine-rich domain containing highly conserved cysteine residues that are critical for disulfide-bond formation (amino acids [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. We also observed a loss of suppression of β-catenin activity by a C31R Tat mutant in the presence or absence of morphine (Fig 4B and 4C).…”

Section: Plos Onementioning

confidence: 60%

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Morphine exposure exacerbates HIV-1 Tat driven changes to neuroinflammatory factors in cultured astrocytes

et al. 2020

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Despite antiretroviral therapy human immunodeficiency virus type-1 (HIV-1) infection results in neuroinflammation of the central nervous system that can cause HIV-associated neurocognitive disorders (HAND). The molecular mechanisms involved in the development of HAND are unclear, however, they are likely due to both direct and indirect consequences of HIV-1 infection and inflammation of the central nervous system. Additionally, opioid abuse in infected individuals has the potential to exacerbate HIV-comorbidities, such as HAND. Although restricted for productive HIV replication, astrocytes (comprising 40-70% of all brain cells) likely play a significant role in neuropathogenesis in infected individuals due to the production and response of viral proteins. The HIV-1 protein Tat is critical for viral transcription, causes neuroinflammation, and can be secreted from infected cells to affect uninfected bystander cells. The Wnt/β-catenin signaling cascade plays an integral role in restricting HIV-1 infection in part by negatively regulating HIV-1 Tat function. Conversely, Tat can overcome this negative regulation and inhibit β-catenin signaling by sequestering the critical transcription factor TCF-4 from binding to β-catenin. Here, we aimed to explore how opiate exposure affects Tat-mediated suppression of β-catenin in astrocytes and the downstream modulation of neuroinflammatory genes. We observed that morphine can potentiate Tat suppression of β-catenin activity in human astrocytes. In contrast, Tat mutants deficient in secretion, and lacking neurotoxic effects, do not affect β-catenin activity in the presence or absence of morphine. Finally, morphine treatment of astrocytes was sufficient to reduce the expression of genes involved in neuroinflammation. Examining the molecular mechanisms of how HIV-1 infection and opiate exposure exacerbate neuroinflammation may help us inform or predict disease progression prior to HAND development.

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Section: Plos Onementioning

confidence: 60%

“…In addition to cytotoxic effects due to direct infection with HIV-1, the CNS represents an environment where secreted viral proteins, cytokines, chemokines, and small molecules can all contribute to neurotoxicity [4,[27][28][29][30][31]. Therefore, proximity to HIV-1 infected cells can result in cell and tissue damage.…”

Section: Introductionmentioning

confidence: 99%

Morphine exposure exacerbates HIV-1 Tat driven changes to neuroinflammatory factors in cultured astrocytes

et al. 2020

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“…Irrespective of whether they become infected, MOR-expressing, HIV or HIV protein-exposed astrocytes release greater amounts of inflammatory cytokines and dysfunction sufficient to harm bystander neurons upon treatment with opiates (El-Hage et al 2005 , 2008b ; Zou et al 2011 ; El-Hage et al 2014 ). MOR-expressing subsets of glia, especially microglia and astroglia, are prominent in driving the interactive opioid and HIV neuropathogenesis (Hauser et al 2007 , 2012 ; Hauser and Knapp 2014 ; Liu et al 2016a ; Chilunda et al 2019 ; Murphy et al 2019 ). When MOR is deleted from glia (astrocytes and microglia), morphine no longer increases the death of Tat-exposed striatal medium spiny neurons (MSNs) (Zou et al 2011 ).…”

Section: Hiv Neuropathology In the Context Of Opioid Use Disorder – Cmentioning

confidence: 99%

“…In primary astrocytes, agonist-selective actions at MOR and KOR can be clearly demonstrated (Bohn et al 2000 ; Belcheva et al 2003 ; McLennan et al 2008 ; Hahn et al 2010 ), and we found that morphine, methadone, and buprenorphine differentially increase ROS and [Ca 2+ ] i alone or following Tat co-exposure (Fitting et al 2014b ). Morphine can enhance HIV-1-induced production of cytokines and specifically chemokines (El-Hage et al 2008a ; Dave 2012 ; El-Hage et al 2014 ), while other opioids including methadone, oxycodone, buprenorphine, and DAMGO can decrease inflammatory function and decrease monocyte migration (Boland et al 2014 ; Carvallo et al 2015 ; Jaureguiberry-Bravo et al 2016 ; Chilunda et al 2019 ).…”

Section: Questions Remaining – Future Directionsmentioning

confidence: 99%

Opioid and neuroHIV Comorbidity – Current and Future Perspectives

Fitting

McRae

Hauser

2020

J Neuroimmune Pharmacol

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With the current national opioid crisis, it is critical to examine the mechanisms underlying pathophysiologic interactions between human immunodeficiency virus (HIV) and opioids in the central nervous system (CNS). Recent advances in experimental models, methodology, and our understanding of disease processes at the molecular and cellular levels reveal opioid-HIV interactions with increasing clarity. However, despite the substantial new insight, the unique impact of opioids on the severity, progression, and prognosis of neuroHIV and HIV-associated neurocognitive disorders (HAND) are not fully understood. In this review, we explore, in detail, what is currently known about mechanisms underlying opioid interactions with HIV, with emphasis on individual HIV-1-expressed gene products at the molecular, cellular and systems levels. Furthermore, we review preclinical and clinical studies with a focus on key considerations when addressing questions of whether opioid-HIV interactive pathogenesis results in unique structural or functional deficits not seen with either disease alone. These considerations include, understanding the combined consequences of HIV-1 genetic variants, host variants, and μ-opioid receptor (MOR) and HIV chemokine co-receptor interactions on the comorbidity. Lastly, we present topics that need to be considered in the future to better understand the unique contributions of opioids to the pathophysiology of neuroHIV. Graphical Abstract Blood-brain barrier and the neurovascular unit. With HIV and opiate co-exposure (represented below the dotted line), there is breakdown of tight junction proteins and increased leakage of paracellular compounds into the brain. Despite this, opiate exposure selectively increases the expression of some efflux transporters, thereby restricting brain penetration of specific drugs.

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“…Among these are a collection of neurological sequelae, collectively known as neuroHIV, which remain prevalent in infected individuals (1)(2)(3)(4). NeuroHIV can be altered and exacerbated by substance abuse (5)(6)(7)(8), one of the most common comorbidities in the HIV-infected population (8)(9)(10)(11)(12)(13)(14)(15). Substance abuse is associated with altered neuropathology, increased neuroinflammation, cognitive decline and increased neuropsychiatric comorbidities, even with effective ART (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Dopamine Levels Induced by Substance Abuse Alter Efficacy of Maraviroc and Expression of CCR5 Conformations on Myeloid Cells: Implications for NeuroHIV

et al. 2021

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Despite widespread use of antiretroviral therapy (ART), HIV remains a major public health issue. Even with effective ART many infected individuals still suffer from the constellation of neurological symptoms now known as neuroHIV. These symptoms can be exacerbated by substance abuse, a common comorbidity among HIV-infected individuals. The mechanism(s) by which different types of drugs impact neuroHIV remains unclear, but all drugs of abuse increase central nervous system (CNS) dopamine and elevated dopamine increases HIV infection and inflammation in human myeloid cells including macrophages and microglia, the primary targets for HIV in the brain. Thus, drug-induced increases in CNS dopamine may be a common mechanism by which distinct addictive substances alter neuroHIV. Myeloid cells are generally infected by HIV strains that use the chemokine receptor CCR5 as a co-receptor, and our data indicate that in a subset of individuals, drug-induced levels of dopamine could interfere with the effectiveness of the CCR5 inhibitor Maraviroc. CCR5 can adopt distinct conformations that differentially regulate the efficiency of HIV entry and subsequent replication and using qPCR, flow cytometry, Western blotting and high content fluorescent imaging, we show that dopamine alters the expression of specific CCR5 conformations of CCR5 on the surface of human macrophages. These changes are not affected by association with lipid rafts, but do correlate with dopamine receptor gene expression levels, specifically higher levels of D1-like dopamine receptors. These data also demonstrate that dopamine increases HIV replication and alters CCR5 conformations in human microglia similarly to macrophages. These data support the importance of dopamine in the development of neuroHIV and indicate that dopamine signaling pathways should be examined as a target in antiretroviral therapies specifically tailored to HIV-infected drug abusers. Further, these studies show the potential immunomodulatory role of dopamine, suggesting changes in this neurotransmitter may also affect the progression of other diseases.

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The impact of substance abuse on HIV-mediated neuropathogenesis in the current ART era

Cited by 50 publications

References 310 publications

Morphine exposure exacerbates HIV-1 Tat driven changes to neuroinflammatory factors in cultured astrocytes

Morphine exposure exacerbates HIV-1 Tat driven changes to neuroinflammatory factors in cultured astrocytes

Opioid and neuroHIV Comorbidity – Current and Future Perspectives

Dopamine Levels Induced by Substance Abuse Alter Efficacy of Maraviroc and Expression of CCR5 Conformations on Myeloid Cells: Implications for NeuroHIV

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