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Dissertation
Effects of morphine and HIV-1 Tat on the blood-brain barrier: implications in HIV disease and HAND
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2020
DOI:
https://doi.org/10.17918/00001027
Abstract
Anti-retroviral therapy (ART) has decreased the severity of HIV-associated neurocognitive disorders (HAND), but more than 50% of HIV-1-infected individuals still suffer from some form of neurologic impairment, however, the underlying mechanism in the development of HAND is still unclear. Factors involved in the onset of neurodegenerative diseases, such as HAND, have been linked to central nervous system (CNS) damage, neuro-inflammation and altered blood-brain barrier (BBB) integrity. Previous studies demonstrated that morphine, a mu-opioid commonly prescribed for pain management of HIV-1-associated neuropathy, increases BBB permeability to cellular passage by modulating expression of cell adhesion molecules (CAMs). We have shown that clinically relevant concentrations of morphine exposure do not significantly alter barrier permeability, influence chemokine gradients, or induce PBMC transmigration across the BBB in two different in vitro models of the BBB, suggesting that morphine use at concentrations used for pain management may not be a contributing factor in the chronic neuro-inflammation observed in HIV-1-infected patients. A potential mediator of chronic neuro-inflammation is the HIV-1 viral protein Tat, which has been shown to cause behavioral abnormalities and neuro-pathologic changes. Tat is expressed even in the presence of ART and is able to enter the CNS through a variety of ways, where Tat can interact with microglia, astrocytes, brain microvascular endothelial cells, and neurons. Although the mechanism underlying the development of HAND is still unknown, other neurodegenerative diseases like Alzheimer's have identified premature cell senescence as a factor in the development of cognitive decline. Although there is no single biomarker to detect senescence, studies performed here have shown that when the two main cells of the BBB, astrocytes and brain microvascular endothelial cells (BMECs) are exposed to chronic, low dose Tat there are increased senescent cells, as measured by SA-beta gal, that are non-proliferative, and this effect is irreversible. The results also showed that chronic, low dose Tat alters the subcellular localization of the tight junction protein ZO-1 in BMECs, which may have further implications in BBB integrity. Finally, using a senescence induced in vitro co-culture system, altered immune cell influx across the barrier was observed, which can contribute to CNS inflammation. Maintaining BBB integrity is central to prevent CNS damaging mechanisms that can culminate in neurodegenerative disorders. These results support the idea that senescence at the BBB may be an underlying mechanism in the development of HAND, and further studies will be essential to develop therapeutics that target senescence at the BBB to mitigate CNS damage.
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Details
- Title
- Effects of morphine and HIV-1 Tat on the blood-brain barrier
- Creators
- Jamie Marino
- Contributors
- Michael R. Nonnemacher (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xv, 240 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991014695542904721