Examination Date

Spring 2-21-2025

Degree

Dissertation

Degree Program

Physiology

Examination Committee

Dr. Scott Edwards, Dr. Patricia Molina, Dr. Tekeda Ferguson, Dr. Rajani Maiya, Dr. Harry Gould

Abstract

Human immunodeficiency virus (HIV) infection impacts multiple organ systems, including nervous system, leading to neurological complications such as HIV-associated neurocognitive disorders (HAND) and HIV-associated neuropathy (HIV-N). Despite antiretroviral therapy (ART), these conditions remain prevalent. Psychiatric comorbidities are also prevalent among people with HIV (PWH), with approximately 30% meeting criteria for alcohol use disorder (AUD), a chronic, relapsing disorder characterized by excessive alcohol consumption. Importantly, alcohol use may exacerbate neurological and psychiatric comorbidities, heightening the vulnerability of PWH to cognitive deficits and pain. This dissertation tested the hypothesis that alcohol exacerbates HIV-associated neurological comorbidities, including HAND and HIV-N, revealing unique interactions among alcohol, cognitive deficits, and pain in the context of HIV across both preclinical models and clinical settings. In a clinical cohort of PWH, at-risk alcohol use was associated with poorer cognitive task performance, particularly among older individuals. Proteomic and phosphoprotein analyses in simian immunodeficiency virus (SIV)-infected rhesus macaques exposed to chronic binge alcohol identified supraspinal (cingulate cortex and hippocampus) alterations in key proteins and pathways potentially contributing to HAND and HIV-N. Regarding pain, recent alcohol use was associated with reduced pain in people with HIV. Similarly, in a rodent model of HIV-N, acute alcohol dose-dependently alleviated HIV glycoprotein 120 (gp120)-associated hyperalgesia at moderate and binge-like doses. These findings suggest alcohol may serve as an effective analgesic in the context of HIV-N, though such use aligns with at-risk drinking patterns that may predispose individuals to AUD. Supporting this, phosphoprotein analyses of rodent brains revealed that acute alcohol administration increased phosphorylation of the glutamatergic NMDA receptor subunit NR1 in the cingulate cortex of males. Furthermore, in PWH, pain was associated with heightened negative affective symptoms, including anxiety and depression, highlighting how chronic pain may elevate the risk for psychiatric comorbidities in this population. Future preclinical studies will explore the mechanisms underlying these associations. Overall, these findings lay the groundwork for future interventional studies, which should take advantage of key molecules identified here to pharmacologically target pathways implicated in these HIV-associated neurological comorbidities and inform the development of safer analgesic alternatives to alcohol in both sexes.

Additional Files
Fitzpatrick-Schmidt, Taylor - Dissertation Report Form.pdf (115 kB)
Dissertation Report Form
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