Date of Award

2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Dennis L. Kolson

Abstract

HIV-associated neurocognitive impairment (HIV NCI) persists in persons living with HIV (PLWH) despite the availability of suppressive combination antiretroviral therapy. Chronic inflammation, oxidative stress, and blood-brain barrier (BBB) disruption are well-known in HIV infection and likely contribute to the development of HIV NCI. Post-mortem and neuroimaging studies in PLWH demonstrate region-specific neuroinflammation, injury, and BBB damage within the brain, indicating that the processes causing HIV NCI might therefore be region-specific. We previously identified the highly inducible antioxidant enzyme heme oxygenase-1 (HO-1) as a potential mediator of HIV neuropathogenesis, showing that HO-1 expression in the prefrontal cortex is reduced in PLWH with HIV NCI compared to both HIV-negative individuals and PLWH without HIV NCI, and this reduction associates with increased CSF HIV RNA, type I interferon-stimulated gene expression, and immunoproteasome expression. HO-1 is expressed throughout the brain, and its expression in brain microvascular endothelial cells has been shown to support BBB functions. This thesis expounds our understanding of the role for HO-1 in HIV neuropathogenesis through two approaches: i) Regional ex vivo analysis of autopsied brains of PLWH without HIV NCI; and ii) manipulation of HO-1 expression in in vitro models of the BBB using human brain microvascular endothelial cells. We show that PLWH without HIV NCI have stable or increased HO-1 expression compared to HIV-negative individuals that associates positively with CSF and plasma HIV RNA consistently throughout the brain. HO-1 expression also associates positively with type I interferon-stimulated gene, immunoproteasome subunit, and endothelial adhesion marker expression. We also noted distinct patterns of neuroinflammation in certain brain regions (posterior cingulate cortex, cerebellum, and globus pallidus). Finally, we demonstrate manipulation of HO-1 expression in a human endothelial cell line and primary human brain microvascular endothelial cells, outlining experimental parameters for future experiments to determine the role for endothelial HO-1 in BBB functioning during HIV infection. Our work suggests that in PLWH without HIV NCI, HO-1 is driven by HIV replication as a component of an inflammatory response throughout the brain, including within the BBB, and that the role for HO-1 within this process can be modeled using primary human cell culture systems.

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