Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Kelly L. Jordan-Sciutto

Second Advisor

Judith B. Grinspan

Abstract

HIV-Associated Neurocognitive Disorders (HAND) continue to afflict approximately half of HIV-infected patients, despite effective viral suppression through antiretroviral therapy (ART). Synaptodendritic damage and white matter pathologies persist; suggesting that toxicities from antiretroviral drugs combined with viral protein effects from CNS reservoirs may be at fault. We hypothesized that ART compounds activate cellular stress pathways leading to dysfunction of neuroglial cells, and that attenuating this stress could ameliorate the dysfunction. Previous studies have demonstrated abundant oxidative stress in HAND

patients, and antiretroviral compounds are capable of generating reactive oxygen species (ROS) to invoke this stress in peripheral cell populations. Here we have established that antiretroviral compounds produce robust levels of oxidative stress in neurons and oligodendrocytes in vitro. In neurons, increased ROS leads to mitochondrial depolarization and apoptotic cell death, which was successfully rescued by treatment with fumaric acid ester monomethyl fumarate (MMF) through activation of the endogenous antioxidant response (EAR). Oligodendrocytes were also negatively affected by specific antiretroviral agents. While not directly toxic, protease inhibitors invoked dose-dependent, reversible decreases in the differentiation from oligodendrocyte precursor to mature oligodendrocytes. ROS were produced, but MMF did not rescue the maturation deficit. Further investigation concluded that MMF, the active metabolite of the drug Tecfidera, which is approved for treatment of Multiple Sclerosis, does not activate the EAR in oligodendrocytes. In fact, the EAR was also not activated by any oxidant compound tested, suggesting that precursor cells which

are known to have low levels of antioxidant/detoxifying enzymes may also be susceptible to oxidative stress because they cannot appropriately activate this response. In vivo, both synaptodendritic damage and myelin loss were observed in rodent models of antiretroviral administration. In higher primates, synaptodendritic damage was evident in SIV-infected pigtail macaques that had received an ART regimen, and myelin basic protein levels were reduced in human HIV patients with HAND who had been ART-medicated for at least one year. Together these results strongly implicate antiretroviral compounds as a contributing factor for the persistence of HAND, and necessitate the development of less toxic antiretroviral therapeutics and adjunctive therapies which can minimize the CNS side-effects of currently utilized compounds.

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