Date of Award

January 2020

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Elijah Paintsil

Abstract

Antiretroviral therapy (ART) has been associated with Metabolic Syndrome (MetS) in patients. MetS is characterized by lipid and cholesterol abnormalities, thus we hypothesized that ART-associated mitochondrial dysfunction and dysregulation of cholesterol biosynthesis genes are in the causal pathway of MetS in people living with HIV (PLWH). We tested this hypothesis using cell culture and peripheral blood mononuclear cells (PBMCs) of HIV treatment-experienced individuals. We observed an increase in apoptosis, a decrease in mitochondrial respiratory function and a decrease in mitochondrial membrane potential in a T lymphoblastoid cell line (CEM). We also conducted quantitative PCR analysis on cDNA derived from patients’ PBMCs and observed an upregulation of 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR) and ATP-binding cassette transporter 1 (ABCA1) in HIV patients on ART compared to healthy controls (p=0.03 and p<0.01, respectively). The increase in HMGCR was confirmed with western blot analysis. Moreover, when we conducted a global analysis of lipid and cholesterol biosynthesis pathways in vitro, we also observed a perturbation of similar genes as were dysregulated in our in vivo study. Thus, ART-associated mitochondrial dysfunction and cholesterol biosynthesis gene dysregulation may predate clinical manifestations of MetS. These could serve as biomarkers for predicting MetS in PLWH and monitoring therapy.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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