Defense Date
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Anatomy & Neurobiology
First Advisor
Pamela E. Knapp, PhD
Abstract
The introduction of combination antiretroviral therapy has significantly improved the longevity and quality of life of people with HIV (PWH). However, neurocognitive impairments along with mood and motor deficits, collectively referred to as HIV-associated neurocognitive disorders (HAND), remain a prevalent concern in this virally suppressed clinical population. Since HAND is considered a progressive disease, therapeutic intervention is critical to combat worsening symptoms. This dissertation aims to explore the underlying mechanisms that contribute to cognitive decline in PWH. Importantly, sex is considered as a biological variable, when applicable, so that we can better understand sexually dimorphic pathways that may influence HIV neuropathology and subsequent treatment. HIV-1 transactivator of transcription (Tat) has been linked to the development of HAND through neuroinflammatory and neurotoxic mechanisms, and emerging evidence suggests that C-C chemokine 5 receptor (CCR5) is a promising target to relieve neurocognitive impairments. To test whether CCR5 is involved in cognitive changes in HAND, we used a non-infectious, transgenic model in which HIV-1 Tat is inducibly expressed. Overall, our findings indicate that males are more susceptible to Tat’s detrimental effects, which we demonstrate can impair spatial learning and memory, as well as increase Tau hyperphosphorylation. Importantly, treatment with maraviroc (MVC), a CCR5 inhibitor, improved the Tat-induced cognitive deficits seen, and hippocampal BDNF processing was enhanced as a result. MVC also selectively reduced phosphorylated tau in the hippocampus of male mice. These molecular changes likely promote a neuroprotective environment where healthy neurons and synaptic processes can thrive, ultimately improving cognitive function. Exploratory studies using a phospho-protein microarray assay detecting over 150 analytes further revealed that MVC may counteract Tat-induced dysregulation of multiple signaling proteins, particularly kinases involved in learning, memory, and synaptic function. Additionally, we explored the influence of CCR5’s ligands on synaptodendritic injury, a key structural component of synaptic function and plasticity. CCL3 appeared to be the most abundant ligand in our in vitro model, warranting further study of the CCL3/CCR5 axis in Tat-induced neurotoxicity. Taken together, the work in this dissertation is meant to expand on our current knowledge of HIV-neuropathology and suggest a novel therapeutic approach involving CCR5 that considers sex-specific mechanisms.
Rights
© Chloe A. Simons
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-10-2025