Effect of antiretroviral therapy on blood-brain barrier integrity and central nervous system inflammation

dc.contributor.advisor Shiramizu, Bruce
dc.contributor.author Kettlewell, Joanna
dc.contributor.department Biomed Science (Tropical Medicine)
dc.date.accessioned 2020-07-07T19:03:47Z
dc.date.issued 2020
dc.description.degree Ph.D.
dc.embargo.liftdate 2022-07-06
dc.identifier.uri http://hdl.handle.net/10125/68912
dc.subject Neurosciences
dc.subject Pharmacology
dc.subject Health sciences
dc.subject antiretroviral therapy
dc.subject Blood-brain barrier
dc.subject HIV
dc.title Effect of antiretroviral therapy on blood-brain barrier integrity and central nervous system inflammation
dc.type Thesis
dcterms.abstract Human immunodeficiency virus type 1 (HIV) enters the central nervous system (CNS) as early as eight days after infection and crosses the blood-brain barrier (BBB) primarily via infected monocytes. Even with suppressive antiretroviral therapy (ART), HIV infection of the CNS causes persistent inflammation, neuronal injury, and BBB breakdown leading to neurocognitive impairment, categorized as HIV-associated neurocognitive disorders (HAND). HAND is a common, debilitating complication of HIV infection. Diagnosing and treating HAND remains challenging. Multiple biomarkers have been proposed to aid in the management of patients with HAND, however, their clinical relevance is undetermined. To address this gap, this study analyzed changes in neuroinflammatory mediators in serum and cerebrospinal fluid (CSF) of HIV-infected study participants with HAND on suppressive ART receiving CCR5-inhibitor maraviroc for 48 weeks. Due to inhibition of the CCR5 receptor, which is important for HIV entry into monocytes, the central hypothesis was maraviroc would reduce neuroinflammation and improve BBB integrity in vivo and in vitro, corresponding to improved neuropsychological performance. The effect of maraviroc on BBB integrity was assessed using both in vivo and in vitro functional assays. The study demonstrated a reduction in some neuroinflammatory mediators, but none that corresponded to improved neuropsychological performance. Decreased in vivo BBB integrity corresponded to increased CSF tumor necrosis factor α and serum calcium-binding protein B of the S-100 protein family. This study also assessed maraviroc as an addition to current pre-exposure prophylaxis (PrEP) therapy [tenofovir disoproxil fumarate, emtricitabine] due to concerns of drug resistance. PrEP with and without in vitro addition of maraviroc showed a reduction in monocyte trafficking across the BBB in two out of three study participants. In vitro PrEP exposure of BBB endothelial cells with and without maraviroc showed an increased presence of tight junction protein occludin. These findings indicate CCR5 inhibition with maraviroc may reduce some neuroinflammation and current PrEP drugs tenofovir and emtricitabine, with and without maraviroc, may be neuroprotective. This study contributes to the field on potential treatment and prevention strategies for HIV infection and HAND. Future research will increase the clinical and translational impact of these findings.
dcterms.extent 110 pages
dcterms.language eng
dcterms.publisher University of Hawai'i at Manoa
dcterms.rights All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.
dcterms.type Text
local.identifier.alturi http://dissertations.umi.com/hawii:10690
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