Author ORCID Identifier


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Document Type


Degree Name

Master of Science


Anatomy & Neurobiology

First Advisor

Kurt Hauser


HIV-1 infection is highly comorbid with opioid use disorder. Prescription and illicit use of opioids are particularly risky for HIV-1 infected individuals due to potential synergistic neurotoxic effects mediated by viral proteins and opioids. Additionally, opiate drug abuse has been shown to exacerbate neuropathogenesis of HIV-1+ individuals. Development of combination antiretroviral therapies (cART) has drastically improved the life expectancy of these patients. Unfortunately, although the severity of neurological and neurocognitive complications has declined, the incidence of HIV-associated neurocognitive disorders (HAND) remains 30-50% in the post-cART era and is worsened by opioid use disorder. HIV-1 proteins, inflammatory mediators, and excitotoxins released and recruited by infected cells lead to sublethal neuronal pathologies, providing the neural basis of HAND. The striatum is a central interface for locomotor and addiction circuits that becomes dysregulated by opioids and is susceptible to harboring high viral loads leading to marked neuropathology in HIV infected individuals. While neurons cannot be infected with HIV, glial cells, such as astrocytes, are preferentially targeted and are the source of many sublethal neuronal effects associated with HAND. While it has been demonstrated HIV viral protein, Tat, is synergistically excitotoxic with morphine through an NMDA receptor-mediated manner, little is known about how HIV-1 Tat interacts with opioids on GABAergic systems. The studies in this dissertation use a glial fibrillary acidic protein (GFAP)-driven doxycycline (DOX)-inducible Tat-transgenic model in female mice that accurately mimics neurological deficits in people living with HIV (PLWH).

Previous studies using this model in male mice showed diminished levels of K+ Cl cotransporter 2 (KCC2) a neuron specific cotransporter that is essential for maintaining low levels of intracellular Cl- required for proper GABAAR-mediated hyperpolarization. Additionally, loss of overall KCC2 levels and KCC2 membrane localization via decreased phosphorylation of Serine 940-KCC2 were rescued by oral gavage of KCC2-enhancing prodrug CLP290. We performed similar studies in female DOX-inducible Tat-transgenic mice and administered a ramping dose of morphine to understand the interactive effects with Tat[MM1] . We found that morphine administration increased anxiety-related behavior and decreased exploration in an open field test. Using western blot analysis to reveal potential changes in expression levels, we found CLP290 increased overall KCC2 levels in the striatum but had no effect on p940-KCC2 or on the immature neuron cotransporter Na-K-2Cl cotransporter 1 (NKCC1). Interestingly, we found that Tat and CLP290 independently diminished levels of calcium-activated chloride channel TMEM16a, suggesting an alternative mechanism where Tat may dysregulate intracellular Cl-. Overall, these studies demonstrate a potential sex difference in the effects of this Tat-transgenic model and CLP290 on KCC2 that should be further investigated in side-by-side studies to better understand KCC2 as a prospective treatment target for HAND and opiate use.


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