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Journal article
Morphine exposure exacerbates HIV-1 Tat driven changes to neuroinflammatory factors in cultured astrocytes
PloS one, v 15(3), pp e0230563-e0230563
25 Mar 2020
PMID: 32210470
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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/beta-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 beta-catenin signaling by sequestering the critical transcription factor TCF-4 from binding to beta-catenin. Here, we aimed to explore how opiate exposure affects Tat-mediated suppression of beta-catenin in astrocytes and the downstream modulation of neuroinflammatory genes. We observed that morphine can potentiate Tat suppression of beta-catenin activity in human astrocytes. In contrast, Tat mutants deficient in secretion, and lacking neurotoxic effects, do not affect beta-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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Details
- Title
- Morphine exposure exacerbates HIV-1 Tat driven changes to neuroinflammatory factors in cultured astrocytes
- Creators
- Kenneth Chen - Department of Biological Sciences, University of the Sciences, Philadelphia, Pennsylvania, United States of AmericaThienlong Phan - Department of Biological Sciences, University of the Sciences, Philadelphia, Pennsylvania, United States of AmericaAngel Lin - Department of Biological Sciences, University of the Sciences, Philadelphia, Pennsylvania, United States of AmericaLuca Sardo - MSDAnthony R. Mele - Drexel UniversityMichael R. Nonnemacher - Drexel UniversityZachary Klase - Department of Biological Sciences, University of the Sciences, Philadelphia, Pennsylvania, United States of America
- Publication Details
- PloS one, v 15(3), pp e0230563-e0230563
- Publisher
- Public Library Science
- Number of pages
- 19
- Grant note
- DP2 DA044550; R03 DA039733 / Public Health Service, National Institutes of Health through National Institute of Drug Abuse (NIDA) T32 MH079785 / Public Health Service, National Institutes of Health through Ruth L. Kirschstein National Research Service Award R01 NS089435 / Public Health Service, National Institutes of Health through National Institute of Neurological Disorders and Stroke (NINDS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; Digital Media; Pharmacology and Physiology
- Web of Science ID
- WOS:000535307600032
- Scopus ID
- 2-s2.0-85082335023
- Other Identifier
- 991019169630204721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Neurosciences