Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Pharmacology

First Advisor

Kelly L. Jordan-Sciutto

Abstract

The advent of combination antiretroviral therapy (ART) in 1996 revolutionized the treatment of HIV/AIDS and significantly decreased the incidence of HIV-associated neurocognitive disorders (HAND), a spectrum of HIV-related CNS dysfunctions ranging from mild cognitive deficits to severe dementia. Although the long-term prognosis for ART-treated, HIV-positive individuals continues to improve, the life-expectancy for this population remains 10-30 years less than that of uninfected individuals. Additionally, the clinical and pathologic presentation of HAND has evolved from a subacute, subcortical encephalitic condition, to a prolonged, cortical, neurodegenerative disease with pathological features that resemble those found in Alzheimer Disease (AD). The specific mechanisms driving these pathological changes remain unknown, although emerging evidence suggests that antiretroviral neurotoxicity may be a significant contributing factor. Here, we examined mechanisms by which antiretroviral drugs induce stress in neurons leading to changes in amyloid precursor protein (APP) processing. Utilizing in vitro models of acute ART exposure, we observed that HIV protease inhibitor (PI)-class ART drugs robustly active the unfolded protein response in primary neurons leading to translational de-repression of beta-site cleaving enzyme 1 (BACE1) by phosphorylated eIF2alpha; and augmented amyloidogenic cleave of APP. These results were corroborated in ART-treated, SIV-infected macaques were we saw increased hippocampal expression of BACE1 AND IN HAND patients where we also found similar increases in BACE1 expression in CA1 and CA3 hippocampal regions accompanied by accumulation of intraneuronal oligomeric Abeta;. Finally, we demonstrate that inhibition of neuronal BACE1 activity in vitro protects cells from hydrogen peroxide and antiretroviral drug-mediated toxicity. From this body of work, we conclude that PI-class antiretroviral drugs play a prominent role in stress activation of CNS neurons leading to aberrant changes in APP processing and potentially contributing to neuronal damage and death in HAND. Lastly, we have identified BACE1 as an important adjunctive therapeutic target in the treatment of chronic cognitive decline in ART-medicated, HIV-positive individuals.

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