DOI
https://doi.org/10.25772/TQYM-SY95
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
MaryPeace McRae
Second Advisor
Joseph McClay
Third Advisor
Kurt Hauser
Fourth Advisor
Dayanjan (Shanaka) Wijesinghe
Fifth Advisor
Matthew Halquist
Abstract
Despite combination antiretroviral therapy effectively suppressing HIV within the periphery, the central nervous system (CNS) remains affected by the virus. Approximately half of people living with HIV will experience HIV-associated neurocognitive disorders (HAND) or neuroHIV. Concurrent opioid use exacerbates neuroHIV by promoting neuroinflammation, viral replication, and potentially altering the antiretroviral concentrations within the brain.
Using a transgenic mouse that expresses the HIV-1 Tat protein, we examined the effects of Tat and morphine on antiretroviral accumulation and distribution and the effects of Tat on morphine accumulation within the brain using infrared matrix-assisted laser desorption electrospray ionization with mass spectrometry imaging (IR-MALDESI-MSI). After Tat induction, antiretrovirals (abacavir, dolutegravir, and lamivudine) ±morphine were continuously delivered for 5 days. Brains were harvested and cryosectioned and slices were imaged using IR-MALDESI-MSI. Multiple brain regions were examined.
The present study revealed that morphine exposure resulted in significantly decreased antiretroviral concentrations in the anterior and posterior brain sections. Interestingly, male mice experienced greater morphine-associated decreases in antiretroviral concentrations than females. The study also assessed whether changes in both antiretroviral and morphine concentrations were associated with areas of activated glia, using GFAP as a marker for glial activation. Differences in antiretroviral concentrations within areas of glial activation differed among treatments based on sex.
The findings from this study highlight the importance of monitoring opioid use in patients with HIV, as antiretroviral medications may become less efficacious within the CNS when co-exposed with opioids, which may contribute to the worsening of neuroHIV.
Rights
© The Author (Austin Matthew Jones)
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
8-2-2023
Included in
Animal Experimentation and Research Commons, Immunology of Infectious Disease Commons, Immunotherapy Commons, Laboratory and Basic Science Research Commons, Medicinal Chemistry and Pharmaceutics Commons, Molecular and Cellular Neuroscience Commons, Other Pharmacology, Toxicology and Environmental Health Commons, Other Pharmacy and Pharmaceutical Sciences Commons, Pharmaceutics and Drug Design Commons, Pharmacology Commons