Date of Award

Fall 2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Dennis L. Kolson

Abstract

Despite antiretroviral therapy (ART), HIV infection promotes cognitive dysfunction and neurodegeneration through persistent inflammation and neurotoxin release from infected and/or activated macrophages. Inflammation and immune activation within both the central nervous system (CNS) and periphery correlate with disease progression and morbidity in ART-treated individuals. Accordingly, drugs targeting these pathological processes are needed for effective, adjunctive therapy. Using our in vitro model of HIV-mediated neurotoxicity, in which HIV infected monocyte-derived macrophages (HIV/MDM) release excitatory neurotoxins, we demonstrate that HIV infection dysregulates adaptive stress responses, including the antioxidant response and the unfolded protein response (UPR). HIV infected macrophages have dramatic reductions in heme oxygenase-1 (HO-1) levels. Activation of the antioxidant response attenuates HIV replication and restoration of HO-1 expression, specifically, reduces neurotoxin release from HIV/MDM, even with robust HIV replication. We propose that dysregulation of the antioxidant response during HIV infection drives macrophage-mediated neurotoxicity and that pharmacological inducers of the antioxidant response could serve as adjunctive neuroprotectants and HIV disease modifiers in ART-treated individuals. Additionally, we found that HIV infection activates the UPR in macrophages, increasing phosphorylated eIF2α in our in vitro system and macrophagic BiP in HAND frontal cortex. Pharmacological induction of the UPR, which attenuates viral replication, enhances macrophage-mediated neurotoxicity. Therefore, processes that induce the UPR in macrophages may enhance neurotoxin production and contribute to pathological processes underlying HAND. Understanding how HIV infection affects adaptive stress responses and neurotoxin production pathways in the macrophage will improve our ability to develop effective adjunctive therapies for the neurological consequences of HIV infection.

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