All ETDs from UAB

Advisory Committee Chair

John Shacka

Advisory Committee Members

Andrew Arrant

Shaida Andrabi

Document Type

Thesis

Date of Award

2022

Degree Name by School

Master of Science (MS) Heersink School of Medicine

Abstract

HIV-associated neurocognitive disorders (HAND) produces serious neurological dysfunction for > 50% of people living with HIV (PLWH). As antiretroviral therapy (ART) has transformed HIV into a chronic disease, and since most ART does not effectively cross the blood brain barrier, HAND is predicted to further increase in prevalence in PLWH. The HIV-Trans-Activator of Transcription (Tat) is known to persist in the central nervous system (CNS) of chronically infected HIV+ individuals. In several preclinical studies, HIV-Tat has been shown to be neurotoxic and important for HIV pathogenesis. Translocator protein (TSPO), an 18 kDa mitochondrial protein, has been shown to be increased via PET imaging studies in HIV+ patients, in association with cognitive dysfunction. The question is, how Tat affects TSPO is still unclear and requires further investigation. To better understand the effects of Tat on TSPO, we utilized an in vitro model of mixed glial cell cultures, together with an in vivo transgenic mice model, in which Tat is expressed at low-levels from the “leaky” Tet-on promoter. In the present study, both in vitro and in vivo models of Tat indicate an increase in TSPO levels, suggesting the potential for TSPO as a novel functional mediator of HIV-Tat-induced neuroinflammation. This result would justify further evaluation TSPO as a candidate therapeutic target for HAND and possibly other age-related neurodegenerative diseases.

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